U54 Grant Summary Statements

Release Date: 08/02/2010

PROGRAM CONTACT: H. Aguila 301-496-7344 [email protected]

SUMMARY STATEMENT ( Privileged Communication )

Application Number: 1 U54 CA156732-01 Principal Investigator

EMMONS, KAREN M PHD

Applicant Organization: DANA-FARBER CANCER INSTITUTE

Review Group: ZCA1 SRLB-3 (O1) National Cancer Institute Special Emphasis Panel Comprehensive Minority Institution Cancer Center Partnership

Meeting Date: 06/29/2010 RFA/PA: CA10-503 Council: AUG 2010 PCC: 6UMB

Requested Start: 09/01/2010

Project Title: U Mass Boston / DFHCC U54 Partnership (1 of 2)

SRG Action: Impact/Priority Score: 29 Human Subjects: 44-Human subjects involved - SRG concerns

Animal Subjects: 10-No live vertebrate animals involved for competing appl. Gender:

Minority:Children:

1A-Both genders, scientifically acceptable 1A-Minorities and non-minorities, scientifically acceptable 3A-No children included, scientifically acceptable

Project Year

1 2 3 4 5

___________ TOTAL

Direct Costs Requested 983,331 952,784 1,046,092 1,019,613 999,835

_______________ 5,001,655

Estimated Total Cost

1,696,854 1,644,142 1,805,156 1,759,463 1,725,334

_______________ 8,630,950

ADMINISTRATIVE BUDGET NOTE: The budget shown is the requested budget and has not been adjusted to reflect any recommendations made by reviewers. If an award is planned, the costs will be calculated by Institute grants management staff based on the recommendations outlined below in the COMMITTEE BUDGET RECOMMENDATIONS section.

1 U54 CA156732-01 2 ZCA1 SRLB-3 (O1)EMMONS, K RESUME AND SUMMARY OF DISCUSSION: The applications, submitted by the Dana-Farber/Harvard Cancer Center and its partner UMASS Boston, describe plans to transition the successful U56 Partnership to a U54. This approach ties a strong cancer treatment and research facility with an educational institution serving URM students; each benefit from the link. Mutually achievable beneficial priorities are chosen. Although the collaboration priorities are clearly articulated; the collaboration has little history of strong community outreach. The applications include 2 pilot projects, 3 research projects, 1 training project, and 1 outreach research project, thus addressing the three target areas. Scientists from each partner are co-PIs on each project, and each project is based at one of the two partners. Investigators demonstrate strength relative to the specific functions they perform within the project. There is expertise within the partnership and generally within at least one of the partners on a particular aspect of the program (e.g. full project, core) in cultural appropriateness related to the specific aspect (e.g. pilot project, full project, training core, etc) The applications include the progression involved in moving pre-pilots to pilots to full projects, focusing on the mentoring and feedback that is provided to develop capacity in scientists. However, distinct methodological challenges are perceived within each of the pilot studies and projects. The plan for achieving objectives is a reasonable one that can be achieved within the 5-year period. A variety of important research questions are chosen, directed toward different and somewhat complementary aspects of oncology research ranging from basic science questions through psychosocial research on end of life care. The investigators are well qualified. Dr. Colón-Carmona is a plant biologist rather than an oncologist; ironically, this is also a strength because he can be brought further into oncology related research over time. Administrative role delineation is described broadly in the DF/HCC application, including generally the responsibilities that fall primarily to UMB, but the UMB application does not pick up with a more detailed description of its specific responsibilities as outlined in the DF/HCC application. The community outreach activities as described in the Administrative Core section seem less well defined than other aspects of the proposal. The UMB leadership team includes the college of science and math dean, the academic support services vice provost, and the nursing and health sciences research associate dean. The DF/HCC PI holds numerous institutional leadership positions. Further, the Executive Committee includes a UMB vice provost for research, and from DF/HCC, the director and deputy associate director of the IECD and the deputy associate director for operations. Both partners commit a variety of institutional resources to the U54. Among them, from DF/HCC, are funds to recruit URM faculty, to support pilot projects, to support partial salary of 5 personnel, to support research training of UMB students, and some limited resources for community outreach. UMB provides funds for faculty start-up as a recruitment incentive, salary support for administrative personnel serving the program, faculty teaching load reductions, and funds to support student research participation. However, Few details are provided about the community outreach resources provided by DF/HCC. Overall application was rated as Excellent. Pilot Project 1- Chromosome Segregation without Cancerous Growth: Kinesin Motor Proteins Studies of the Spindle Assembly Checkpoint (SAC) in A. thaliana will give insight into this important growth regulatory mechanism in plants, where it has been little studied. Comparison of the SAC in plants with the corresponding mechanism in animal cells will help illuminate the most important central features of the mechanism. However, it is not clear whether the details of the SAC in plants will be relevant to the often subtle derangements associated with oncogenesis in animal cells. This Pilot Project was rated as Very Good. HS10, A10 Pilot Project 2- Racial Disparities in Depression and Mental Healthcare Utilization in Lung Cancer

1 U54 CA156732-01 3 ZCA1 SRLB-3 (O1)EMMONS, K This proposed pilot project represents an effort to address racial disparities in mental healthcare services, which is an understudied aspect of cancer care. The primary aim of the study is to examine possible racial disparities in depression and mental health service utilization in lung cancer patients. The significance of the study is that there is a need to identify racial disparities in depressive symptoms in lung cancer patients. It is not clear, however, how the theoretical framework self-regulatory and explanatory models will be utilized in the quantitative study or to connect the two studies. The investigative team seems well suited to conduct the proposed study, though the leadership plan is unclear. This Pilot Project was rated as Excellent. HS30, G1A, M1A, C3A, A10 PROJECT 1 - Latino End-of-Life Care: Patient, Provider, & Institutional Effects This is a critical issue to address in Latino health delivery disparity. This study will allow the first careful analysis of the relative contributions of patient, provider and institution to the problem. The study builds on results from Coping with Cancer (CwC) study that revealed that racial/ethnic disparities in EOL care exists. Clinical impact features of the project are not well described, thus is it difficult to fully capture the potential novelty. The investigative team is outstanding and the lead investigators have worked together on several previous studies. Details about the subject interview procedures to ensure protections are not provided. This Project was rated as Very Good. HS44, G1A, M1A, C3A, A10 PROJECT 2 – In vivo analysis of signaling dynamics in the Notch interaction network The proposed project is significant. The project – to tag the genomic copies of the Notch and Delta, and then exploit strains containing those tagged genes – will provide important tools for analysis of the Notch system in Drosophila. The investigators have worked together in a productive relationship for several years, with good reason to think they can continue. One weakness of the approach is inevitable. Tagging genes always runs the risk of altering the behavior of the gene product at the biochemical and cell biological level. The investigators include several tests of the genetic competence of the tagged genes, but whether the observed biochemical and cell biological behavior is largely normal is difficult to ascertain. This Project was rated as Outstanding. HS10, A10 PROJECT 3 - Covalent Fluorescent Probes for Cancer Cell Detection This proposed is the extension of an ongoing collaboration between Drs. Nathanael Gray (Dana Farber Cancer Institute), Priscilla Yang (Harvard Medical School) and Wei Zhang (UMass Boston). All three are also members of the Dana Farber/Harvard Cancer Center. One of the strong points of this grant application is that each Co-Pl is responsible for one of the three Specific Aims allowing the project to be benefited by the balanced skills and expertise that each person and their subsequent institution brings to the partnership. The Gray laboratory is responsible for the affinity purification of kinase targets, for which the laboratory does not seem to have any particular expertise (the three references from graduate student days notwithstanding).The applicants repeatedly wander away from the novel thread to previously designed inhibitors that properly belong in other projects, but are presented here under the guise of “controls”. This Project was rated as Excellent. HS10, A10 PROJECT 4 - Nursing Post-Doctoral Program in Cancer and Health Disparities This is a promising innovative, well designed, and significant project that builds exceedingly well with prior U-56 efforts and outputs. The project contributes to a well-trained nursing workforce in cancer health disparities research and adds to the pipeline of nurse scientists. This project is led by key senior leaders, Dr. Patricia Reid-Ponte, Senior VP Nursing and Patient Care Services at DFCI, and Dean Glazer at UMB. An attractive element of the post-doctoral training is the tailored nature of the program; however, a draft list of topics that would be covered to show depth and breadth of cancer health disparities topics to be addressed is not provided. No information is provided to determine how the program will ensure that at least 50% of mentees are minorities. This project is led by key senior leaders, Dr. Patricia Reid-Ponte, Senior VP Nursing and Patient Care Services at DFCI, and Dean

1 U54 CA156732-01 4 ZCA1 SRLB-3 (O1)EMMONS, K Glazer at UMB. The investigators state that there are no human subjects. Depending on sources of data and potential use of data, there may be need for IRB. This Project was rated as Outstanding. HS44, G1A, M1A, C3A, A10 PROJECT 5 - Promoting Utilization of Cancer Early Detection Methods among Latinos in Church: The primary aim of the study is to develop an organizational-level intervention to enable Latino faith-based organizations, Catholic ones with >60% Latinos, to adopt, implement and sustain evidence-based interventions to address cancer disparities among Latinos. The Co-PIs, Drs. Allen and Torres, and research team seem extremely well positioned to conduct the proposed study. Previously completed work suggests that both community and institutional resources are in place to accomplish this project. The project builds upon the resources and expertise of the training core and survey and statistical methods core. However, the outreach aspect of the overall U54 seems to still be at a very developmental point. This project should further and strengthen this effort, but may be hampered by the lack of a strong outreach focus of the overall program and partnership. This Project was rated as Excellent. HS30, G1A, M1A, C3A, A10 CORE 1 - Career Development Plan The career development plan provides strong rationale for having a primary mentor and includes training in conduct of research. The application also includes good descriptions of institutional support for some career development plans. However, it does not mention what to do in cases of conflict between mentor and mentee, how to evaluate success of mentoring plan progress, or how goals will be attained; specificity of goal-attainment not included in many plans. Some plans have little discussion of primary mentors.This Core was rated Satisfactory CORE 2 - Resource/Infrastructure Development Core The proposed resources in these Cores are well-described and will contribute significantly to a successful completion of the project. The experience, leadership, organizational abilities, and expertise of the leadership staff are documented and are adequate to conduct the Core. This Core was rated as Exceptional. CORE 3 - Planning and Evaluation Core Planning structures/committees are in place to undertake various aspects of planning, including 1) an established Executive Committee that meets monthly, 2) an Internal Advisory Committee with 3 distinct focus-related subcommittees which foster collaboration and research expansion, provide internal review and evaluation of developmental and pilot projects, and 3) a Program Steering Committee that provides external annual evaluation. Planning activities are identified related to fostering collaborative research, develop the training program, and developing outreach, basic science, population science, and training. However, a discussion of how new proposals are identified and reviewed to make sure the overall “package” meets the goals of the partnership is not provided. This Core was rated as Satisfactory. CORE 4 - Administrative Core The Administrative Core is comprised of two components, one based at DF/HCC and the other at UMB. At DF/HCC, the Core includes both scientific and administrative leadership. The application includes significant evidence of administrative integration of the proposed partnership (a flow chart) and the past success of the partnership indicates that the programs are integrated. The roles of the individual administrators at each partner are also well described. The proposed quality of organizational and an administrative structure are adequate for the effective attainment of the priorities and objectives of the Partnership with the inclusion of the changes described in the application. Although communication

1 U54 CA156732-01 5 ZCA1 SRLB-3 (O1)EMMONS, K process is well established, description of challenges or conflicts and solutions are not described in appropriate details. This Core was rated as Exceptional. DESCRIPTION (provided by applicant): This submission is in response to CAI 0-503 Comprehensive Partnerships to Reduce Cancer Health Disparities. This application, submitted by the Dana-Farber/Harvard Cancer Center and its partner UMASS Boston, describes plans to transition the successful U56 Partnership to a U54: From Its Inception, the Partnership has been based on strong Institutional support, significant personal commitment of the leadership, and a belief in the institutional benefit that would be derived from a successful partnership. Two key tenets underlie the formation of our Partnership: a) a common and Intense Interest In addressing the problem of racial, ethnic, and socioeconomic disparities in cancer; and b) a belief that through the partnership, each partner will achieve benefits that neither could achieve on Its own. Through careful planning, a mature, solid, and committed partnership has evolved which has been transformative for both Institutions. This application provides extensive evidence of the ways these tenets have been operationalized and the resulting benefits, which have been substantial for both institutional partners. In addition to robust Administrative and Planning & Evaluation Cores, and two shared resources (Training Core and Statistical and Survey Methods Core), the application includes rigorous and innovative science, representing basic, clinical, and population science, as well as an innovative post-doctoral training program In nursing and health disparities. The Partnership has strong and enthusiastic personal and Institutional support from the leaders of the respective institutions. The Partnership has well-established communication, leadership, and evaluation in place, and Is guided by an outstanding, external Program Steering Committee. This Partnership is fully prepared to move to the U54 mechanism. CRITIQUE: The written critiques of individual reviewers are provided in essentially unedited form in the "Critique" section below. Please note that these critiques were prepared prior to the meeting and may not have been revised subsequent to any discussions at the review meeting. The "Resume and Summary of Discussion" and Overall Critique sections above summarize the final opinions of the committee. CRITIQUE 1: Significance: 1 Investigator(s): 1 Innovation: 2 Approach: 2 Environment: 1 Overall Impact of Project: Strengths:

• Ties a strong cancer treatment and research facility with an educational institution serving URM students; each benefit from the link.

• Well chosen, mutually beneficial priorities held by the collaboration; all are achievable. • Collaboration introduces undergraduate URM students to cancer disparities research and

enhances the possibilities of these individuals pursuing graduate work in cancer disparities. • Collaboration Priorities are clearly articulated and include:

(a) to develop rigorous, interdisciplinary programs of collaborative research (b) expand focused training opportunities for URM students, nursing students and

postdoctoral fellows (c) increase community outreach and cancer education (d) develop shared mechanisms for faculty recruitment, engagement and career

development

1 U54 CA156732-01 6 ZCA1 SRLB-3 (O1)EMMONS, K

• Application presents data showing progress toward each of these priorities, documenting the development of the collaboration toward these ends over time.

Weaknesses • No major weaknesses noted.

Core Review Criteria: 1. Significance: Strengths:

• A variety of important research questions are chosen, directed toward different and somewhat complementary aspects of oncology research ranging from basic science questions through psychosocial research on end of life care.

• Ties a strong cancer treatment and research facility with an educational institution serving URM students.

• Brings together two strong leaders in different career phases into a collaborative effort; each fits their academic environment well and shows signs of strong leadership.

• Well chosen, mutually beneficial priorities held by the collaboration; all are achievable. • Collaboration introduces undergraduate URM students to cancer disparities research and

enhances the possibilities of these individuals pursuing graduate work in cancer disparities. • Collaboration Priorities are clearly articulated and include:

1) to develop rigorous, interdisciplinary programs of collaborative research 2) expand focused training opportunities for URM students, nursing students and postdoctoral fellows 3) increase community outreach and cancer education 4) develop shared mechanisms for faculty recruitment, engagement and career

development • Application presents data showing progress toward each of these priorities, documenting the

development of the collaboration toward these ends over time. Weaknesses:

• Distinct methodological challenges exist within each of the pilot studies and projects. 2. Investigator(s): Strengths:

• Adan Colón-Carmona (UMass Boston plant biologist) co-leads a well qualified team of diverse researchers from UMass-Boston and the Dana Farber Cancer Institute.

• Karen Emmons (DF/HCC) has been involved in developing and nurturing partnership from start. Dr. Pellman provides excellent mentorship for Dr. Colon-Carmona as he advances his scientific skills and productivity into oncology research.

• Dr. Emmons provides excellent mentorship on leadership of a diverse research team. • Individual projects show experienced and diverse investigators on programs.

Weaknesses: • Dr. Colón-Carmona is a plant biologist rather than an oncologist; ironically, this is also a

strength because he can be brought further into oncology related research over time. • The collaboration has little history of strong community outreach.

3. Innovation: Strengths:

• Scientific studies explore cogent and important questions in reasonably innovative ways. • Methodology should yield useful results in studies proposed. • Demonstrated track record for collaboration. • $16 million dollars in research grants received by point of application. • $13 million dollars in training grants received.


• Collaboration has led to funding by State of Massachusetts for Center for Personalized Cancer Therapy at UMass Boston and funding of Brann Endowed Chair.

• Collaboration has led to establishment of accelerated BSN- to-PhD program in Nursing at UMB • Proposed postdoctoral training program will benefit nurses wishing training and DFCI as clinical

and research institution. • Proposal further grows the scientific and leadership skills of Dr. Colón-Carmona as a cancer

researcher extending past recent sabbatical with Dr. Pellman. • Evidence of actualization of what collaboration needs to continue to thrive. • Careful selection of solid next steps for nursing post-doctoral training program. • Potential to train doctoral researchers in 8 fields at UMB. • Meaningful contribution of resources from each institution.

Weaknesses: • Some innovative measures have not been validated fully (ie Spanish translations of English

language measures. 4. Approach: Strengths:

• Overall strategy for building and maintaining collaboration appear strong and effective. • SSM Core is strong and available to all. • Communication among collaborators has brought together mutli-talented teams with diverse

skills and has intermingled more junior and more senior investigators while offering opportunities for undergraduates and graduate students to become immersed in cancer disparities research methods.

• Careful documentation of communication problems that have occurred and been noted to allow better future functioning (see Lessons Learned in Emmons proposal).

• While methodological flaws were found in each of the projects, none reached the level of fatal flaw.

Weaknesses: • No articulation of how conflict will be handled should it occur between mentors and trainees, or

research collaborators. 5. Environment: Strengths:

• Dana Farber is an excellent cancer facility with a very strong clinical research tradition and presence.

• Excellent cancer research laboratory space, computer access and human research space; all made available to UMB researchers.

• UMB has diverse students, faculty and is eager to collaborate. • Both environments are committed to collaboration and demonstrate that fiscally to the extent to

which they are able. • UMB gaining new research space soon. • Center for Personalized Therapy being established as described above.

Weaknesses: • Difficulty supporting research intensive program within UMass-Boston, a Research II institution,

with adequate teaching release time. • Less tradition of community outreach at UMB than might be desired. • Role of CHE not well articulated.

Overall Evaluation and the Partnership Integration a. Commitment from the Institutional Leadership: Strengths:

• Recent relevant Dean recruitments at UMB have emphasized collaboration as an attractant.


• Karen Emmons holds Dean of Research appointment at Harvard School of Public Health now. • Appropriate demonstrations of commitment in personnel, time, money, and space at both

partners. Weaknesses

• No major weaknesses noted. b. Scientific and Administrative Leadership: Strengths:

• Recent relevant Dean recruitments at UMB have emphasized collaboration as an attractant. • Karen Emmons holds Dean of Research appointment at Harvard School of Public Health now. • Appropriate demonstrations of commitment in personnel, time, money, and space at both

partners. Weaknesses

• Emmons’ appointment as Associate Dean for Research may make time commitment for program more difficult.

c. Scientific Integration: Strengths:

• Appears to have adequate administrative support of program at each of the sites. • Administrative structure of program well formed and experienced. • Lesson learned noted in Emmons proposal suggests new and unexpected problems will be met

with patience and creative problem solving, all based on strong communication. • History of collaboration has been quite successful to date. • It is clear that each institution understands what it gains from the collaboration and that the

benefits to each are substantial. • There is variety among the methods and aims of the proposed pilots and programs. • They are all coherent and sufficient as joint efforts. • The partnership has already demonstrated that it is successful in meeting objectives moving

toward reducing cancer care disparities; this program will build further on the existing success. Weaknesses:

• There is no single compelling core to all of the programs and pilots. d. Administrative Core Strengths:

• The applications show careful planning to ensure administrative voice on each partner’s part. • The applications show substantial commitment to ongoing and extensive communication. • Recent relevant Dean Recruitments at UMB have emphasized collaboration as an attractant. • Karen Emmons holds Dean of Research appointment at Harvard School of Public Health now. • Appropriate demonstrations of commitment in personnel, time, money, and space at both

partners. • Administrative Core appears well planned and implemented; partners well integrated. • Quality of proposed administrative structure appears strong and has history of success. • Proposed budget appears appropriate to needs of program.

Weaknesses: • Extensive commitment of Deans may mean that this program may often have to take only time

available. CRITIQUE 2: Significance: 3 Investigator(s): 2 Innovation: 2

1 U54 CA156732-01 9 ZCA1 SRLB-3 (O1)EMMONS, K Approach: 3 Environment: 2 Overall Impact of Project: Strengths:

• The U56 partnership has many demonstrated accomplishments that are very much in line with the goals of the Comprehensive Partnerships, among them strong mentoring and developmental relationships, effective organizational and oversight structures, complementary strengths of partners, and synergy and complementarily between partners within cores and research project activities.

• U54 planning seems to be very consistent with, and progressing from, the foundation laid by the U56.

Weaknesses: • Processes and procedures for Core functioning are minimally detailed, requiring the reviewer to

depend on previous successful outcomes for evaluating future potential for success. Core Review Criteria: 1. Significance: Strengths:

• Has leveraged the U56 to produce $13.6 million in training grants from pre-collegiate to postdoc and including research training ranging from proteomics to community based participatory research and also generating qualified applicants for other training opportunities; thus significant contribution to trained researcher pool.

• Nineteen U56 funded research projects from biomedical to clinical and community intervention focus and $16 million in research awards (with another $10 million pending) including two R01s

• Successful faculty researcher recruitment and hires at UMB, extending potential for further research growth in area of cancer and health disparities

• Potential of the Center for Personalized Cancer Therapy at UMB for identifying and treating cancer subtypes.

Weaknesses: • No major weaknesses noted.

2. Investigator(s): Strengths:

• Investigators demonstrate strength relative to the specific functions they perform within the project.

• There is expertise within the partnership and generally within at least one of the partners on a particular aspect of the program (e.g. full project, core) in cultural appropriateness related to the specific aspect (e.g. pilot project, full project, training core, etc).

• Reported successes in developmental projects and process used in U56 for progression from pre-pilots to full research projects suggest that training approach for researchers engaged in independent research is effective.

• UMB experience with training from pre-college through post-doctoral brings strength in culturally appropriate training approaches to research training strength of DF/HCC.



• For the community outreach research project, the PI applies a church based intervention approach that has been used extensively in the African American community to Latino churches, with innovations associated with the use of a complex conceptual framework that tests capacity building in the churches as a means to disseminate evidence based cancer information.

1 U54 CA156732-01 10 ZCA1 SRLB-3 (O1)EMMONS, K Weaknesses

• No major weaknesses noted. 4. Approach: Strengths:

• The population and community based research projects were adequately described, to use appropriate designs, and to address limitations.

• The career development and mentoring plans for investigators are described in good detail. Weaknesses:

• Translation and dissemination of findings to other partnerships was generally not discussed. 5. Environment: Strengths:

• New shared training/research space on the UMB campus, which also helps address space constraints of DF/HCC.

• DF/HCC shared resources (cores) available to UMB scientists enhancing their cancer research capacity.

• New cancer research focus for UMB’s ethnic institutes, with initial efforts focused on community screening, and now plans to expand to intervention research.

• Establishment of the Center for Personalized Cancer Therapy at UMB, with potential for identifying and treating cancer subtypes.

Weaknesses: • Biomedical training opportunities beyond the baccalaureate level at UMB appear to be a

challenge. Overall Evaluation and the Partnership Integration a. Commitment from the Institutional Leadership: Strengths:

• The UMB leadership team includes the college of science and math dean, the academic support services vice provost, and the nursing and health sciences research associate dean. The DF/HCC PI holds numerous institutional leadership positions. Further, the Executive Committee includes a UMB vice provost for research, and from DF/HCC, the director and deputy associate director of the IECD and the deputy associate director for operations.

• Both partners commit a variety of institutional resources to the U54. Among them, from DF/HCC, are funds to recruit URM faculty, to support pilot projects, to support partial salary of 5 personnel, to support research training of UMB students, and some limited resources for community outreach. UMB provides funds for faculty start-up as a recruitment incentive, salary support for administrative personnel serving the program, faculty teaching load reductions, and funds to support student research participation.

Weaknesses: • Few details are provided about the community outreach resources provided by DF/HCC.

b. Scientific and Administrative Leadership: Strengths:

• The investigators emphasize the stable leadership of the two institutional PIs, and provide ample evidence of the success of the U56, suggesting able leadership.

• The scientific leadership includes scientists with suitable qualifications including research grants and publications, to support the various endeavors of the partnership, including the individual research projects as well as the cores. Letters indicating mentoring support for six project scientists with U54 career development plans are included and appear appropriate. The productivity of the U56 provides further indication that this partnership is able to leverage its resources to obtain additional research and training funding.


• DF/HCC provides substantial funds to support URM recruitment by its partners, as well as providing its resources to support recruitment by UMB.

• UMB views the Center for Personalized Cancer Therapy (CPCT) as a powerful faculty recruitment tool.

• UMB has created an endowed chair devoted to partnership related activities, for which it is now searching.

Weaknesses: • DF/HCC’s ability to recruit faculty is limited by the fact that as a consortium cancer center, it

cannot create faculty positions. • UMB indicates plans to recruit some four to six, plus five additional faculty who would be

connected in various ways to the U54. However, details provided on recruitment approaches, other than the draw of the CPCT, are limited.

c. Scientific Integration: Strengths:

• The following examples of accomplishments of the U56 which also offer promise of growth and potential for the U54, demonstrate coordination, synergy and mutual benefits between institutional partners:

o New shared training/research space on the UMB campus, which also helps address space constraints of DF/HCC

o DF/HCC shared resources (cores) available to UMB scientists enhancing their cancer research capacity

o New cancer research focus for UMB’s ethnic institutes, with initial efforts focused on community screening, and now plans to expand to intervention research

o Establishment of the Center for Personalized Cancer Therapy at UMB, with potential for identifying and treating cancer subtypes

• The applications include 2 pilot projects, 3 research projects, 1 training project, and 1 outreach research project, thus addressing the three target areas. Scientists from each partner are co-PIs on each project, and each project is based at one of the two partners.

• The applications include the progression involved in moving pre-pilots to pilots to full projects, focusing on the mentoring and feedback that is provided to develop capacity in scientists

• The success and productivity demonstrated in the U56 phase suggests that the plan for achieving objectives is a reasonable one that can be achieved within the 5-year period.

• The mutual enhanced capacity achieved and demonstrated in the U56 phase provide, support that the overarching goals of the CPP for each partner can be achieved. Further, there is evidence of complementarily and real contributions provided by each partner in each aspect of the program as it is planned and described in the applications, which should provide the same type of mutual capacity building demonstrated in the U56.

Weaknesses: • Outreach activities planned for the community health educator are not well-developed.

d. Administrative Core Strengths:

• The committee structure indicates good integration of administrative roles and division of oversight responsibility between the partners.

• U56 productivity suggests an effective administrative structure that remains in place. • Administrative support provided to cores and investigators is well delineated.

Weaknesses: • Administrative role delineation is described broadly in the DF/HCC application, including

generally the responsibilities that fall primarily to UMB, but the UMB application does not pick up with a more detailed description of its specific responsibilities as outlined in the DF/HCC application.


• The community outreach activities as described in the Administrative Core section seem less well defined than other aspects of the proposal.

COMMITTEE BUDGET RECOMMENDATIONS: The budget was recommended as requested. Pilot Project 1 - Aberrant Chromosome Segregation without Cancerous Growth: Kinesin Motor Proteins (Description as provided by applicant) Properly segregating genetic material in mitosis and meiosis is crucial for cell survival and normal development. During cell cycle progression in mitosis, distinct molecular mechanisms ensure condensation, orientation and segregation of replicated chromosomes. The mitotic microtubule spindle array, its interaction with chromosomes via the kinetochore and the multiple components of the spindle-assembly checkpoint (SAC) guarantees that the structural and chronological orchestration of events happens normally and repetitively in actively dividing cells. The SAC proteins, including the kinesin motor protein centromere associated protein E (CENP-E), are localized at the kinetochore of unattached mitotic chromosomes. While it is clear that depletion of CENP-E in cells leads to chromosome instability and subsequently tumor formation, how CENP-E's role in the congression of mono-oriented chromosomes to the metaphase plate is integrated into overall SAC function remains poorly understood. Moreover very little is known about the SAC in plants. The proposed pilot project will test three key hypotheses in plant cell cycle control. The first evaluates whether plant {Arabidopis thaliana) CENP-E is involved in growth control via the SAC, more specifically in regulating the timing of chromosome metaphase plate alignment. Second, the loss of CENP-E function will lead to aberrant chromosome alignment, and support one of the following models: 1) CENP-E will attach chromosomes to bipolar spindle microtubule fibers and align chromosomes at the metaphase plate; 2) CENP-E will move chromosomes attached to monooriented spindle microtubule fibers towards the metaphase plate, 3) plant CENP-Es can do both 1 and 2, and this will be revealed with the analysis of both AtCENP-EI and AtCENPE2 from Arabidopsis, or 4) CENP-E in plants does neither 1 nor 2, but rather has a distinct function. Thirdly, cytokinesis is not affected in loss-of function mutants, indicating that CENP-E functions primarily in prometaphase and metaphase of the cell cycle. Testing the above hypotheses will not only advance the plant cell cycle field but also contribute to the general understanding of motor protein function, check point control, ploidy and cancer development. The collaboration between Adan Colon-Carmona, PhD, and David Pellman, MD, provides a unique opportunity for Dr. Colon- Carmona's career development, and the training of students will be central to the project. CRITIQUE 1: Significance: 5 Investigator(s): 2 Innovation: 4 Approach: 4 Environment: 1 1. Significance: Strengths:

• In mouse models. it has been shown that aneuploidy contributes to tumorigenesis. A more thorough understanding of the basic mechanisms underlying the maintenance of the fidelity of chromosomal segregation will contribute further to the understanding of this aspect of tumorigenesis.

Weaknesses: • Although a common characteristic of malignancy, it remains controversial as to the relative

contribution of aneuploidy has to do with human malignancy.


• Checkpoint dysfunction (the focus of the application) driven chromosomal instability and aneuploidy does not appear to be important as a primary cause of human cancer.


• The Principal Investigator, Dr. Pellman, is a highly accomplished investigator in the field of chromosomal instability, aneuploidy and cancer. Dr. Colon-Camona is very experienced in plant biology, providing the expertise with the proposed model.

Weaknesses: • Dr. Colon’s experience has been restricted to plant biology, with limited experience in cancer

research. Furthermore his plant biology expertise has not focused on the area of mitosis, but rather cytoskeleton, cell signaling, and plant-bacterial interactions.


• Studying basic biology of cellular processes relevant to cancer in a non-conventional model. • The plant model is innovative in that in mammals there is a single CENP-E gene and loss of this

gene is lethal, whereas in the plant model there are 2 genes and the loss of one is not lethal which could provide an opportunity to study the mechanistic role of this protein in more detail.

Weaknesses: • The contribution of the information learned in this model will not likely advance knowledge

relevant to human cancer much beyond what is already known. It has already been published that in mammalian cells CENP-E stabilizes microtubule capture by kinetochores and when CENP-E is defective aneuploidy can occur.

• The fact that there are 2 genes in the plant (that appear to have different functions since each of the single mutants has a different phenotype), and 1 in mammals raises the question of being able to extrapolate the plant findings to mammalian cells.

4. Approach: Strengths:

• Confocal time lapse imaging of spindle and kinetochore stained cells will be used to observe how and when chromosomes arrive at the metaphase plate in CENP-E2 depleted cells.

• Single and double CENPE mutants will be studied first phenotypically, with experiments to examine chromosomes arriving at the metaphase plate and ploidy.

Weaknesses: • The experiments described are largely phenotype observations, with little in terms of mechanistic

experiments. • The rationale for looking at defects in gametophyte and embryo development in the single and

double mutants in relation to tumor biology is not clearly presented. • The investigators state that they will examine the role of gibberellin but provide no information on

the experiments that they will perform to study this. • Creating transgenic plants that over-express CENP-E will contribute minimally to knowledge of

the mechanism of CENP-E function. • In general, potential pitfalls and alternatives are not considered.

5. Environment: Strengths:

• The environment is exceptional. Weaknesses:

• No major weaknesses noted. CRITIQUE 2:

1 U54 CA156732-01 14 ZCA1 SRLB-3 (O1)EMMONS, K Significance: 3 Investigator(s): 2 Innovation: 4 Approach: 6 Environment: 4 1. Significance: Strengths:

• Studies of the Spindle Assembly Checkpoint in A. thaliana will give insight into this important growth regulatory mechanism in plants, where it has been little studied.

• Comparison of the SAC in plants with the corresponding mechanism in animal cells will help illuminate the most important central features of the mechanism.

Weaknesses: • It is unclear whether the details of the SAC in plants will be relevant to the often subtle

derangements associated with oncogenesis in animal cells. 2. Investigator(s): Strengths:

• Prof Colon-Carmona has used a sabbatical leave to establish this project, making his personal acquaintance with its vagaries a strength.

• The relationship with Prof Pellman is strong and likely to be useful Weaknesses:

• No major weaknesses noted. 3. Innovation: Strengths:

• The intention to develop the plant system for this regulatory mechanism is novel in a broad sense.

• The availability of two CENP-E proteins (so that deletion of one is not lethal) is a valuable tool. Weaknesses:

• Because the study of the SAC is well along in animals, the thinking and questions from those systems tends to confine the thinking in this system.


• The tools available (single mutants, GFP-labeled histones and tubules) are very powerful. • The microscopic methodologies are already in place, with significant results generated.

Weaknesses: • Although justifiable in a system which is still being characterized, the proposed experiments are

largely exploratory, or unfocussed. For example, Specific Aim1 sets out to address a question of whether CENP-E engages mono-oriented or bi-oriented microtubules, and the initial proposal to carefully visualize the orientation of captured chromosomes is a start on this problem. However, the second experiment (to compare aneuploidy in different meristem regions) is interesting, but it is unclear how it tests any particular model of CENP=E function.

• The general phenotypic analysis of CENP-E mutants (single and, if possible, double) might be useful, but there is no indication of any purpose for which it might be useful, other than “further analysis of the complex phenotype.”

• Similarly, the third Aim, addressing aneuploidy versus polyploidy in mutants, is driven by the argument over the model of Kapoor et al in animal cells, but the fundamental differences in cytokinesis mechanisms between plants and animals, and the natural proclivity in plants for generation of polyploidy cells, weaken the applicability of the plant cell system for addressing this issue.

1 U54 CA156732-01 15 ZCA1 SRLB-3 (O1)EMMONS, K 5. Environment: Strengths:

• This experimental system, particularly as mounted in this application, is an ideal teaching environment for conveying modern genetic and molecular biological principles and practices.

• The collaboration with an established cell cycle control laboratory is idea for guiding initial characterization of the plant system.


CRITIQUE 3: Significance: 3 Investigator(s): 2 Innovation: 3 Approach: 3 Environment: 2 1. Significance: Strengths This project has a high level of significance. CENP-E is involved in at least three crucial mechanisms during mitosis: 1) it permits interactions between chromosomes and spindle microtubules (Putkey et al., 2002) in addition to kinetochores fibers (Kapoor et al., 2006), both necessary for chromosome congression; 2) it transduces the state of chromosomes capture by inducing a SAC "wait-anaphase" response even when a single chromosome is not attached (Howell et al., 2003); and 3) it releases the SAC via BubRI/BubR3 interactions when all chromosomes are bi-oriented, allowing cells to progress into anaphase (Mao et al., 2005). Given that CENP-E is a required component for the spindle-microtubule kinetochore anchoring and the "wait-anaphase" switch, it is hypothesized then that CENP-E serves as a sensor and amplifier of the SAC by linking the state of chromosomes capture to mitosis progression. Weaknesses While most studies concerning plant specific microtubule structures involve the analysis of early prophase (e.g. PPB formation) and cytokinesis (e.g. phragmoplast formation) (Muller et al., 2009), little attention has been given to the fundamental control points of mitosis, such as mitotic chromosome behavior leading to the SAC. 2. Innovation: Strengths While the methodology is not innovative, the approach to the question is innovative. There is only one gene in vertebrates that encodes for CENP-E, and complete loss-of-function is lethal. This makes it difficult to dissect out possible subtle difference in function, such as in chromosome segregation and/or chromosome capture. Studying the function of CENP-E in plants in the context of development provides an opportunity to address mechanistic as well as evolutionary questions, because CENP-E loss-of-function in either of AtCENP-E is not lethal (see preliminary data). Moreover, the proposed work will be done with the most prominent of the plant model systems, Arabidopsis thaliana, for which molecular and genetic resources are available. Weaknesses No major weaknesses noted. 3. Investigators:

1 U54 CA156732-01 16 ZCA1 SRLB-3 (O1)EMMONS, K Strengths Both investigators are well published and experienced researchers in this area. They have a previously established working relationship and have demonstrated productivity. Weaknesses No major weaknesses noted. 4. Approach: Strengths The research approach is very clearly described and is based on logical scientific principles. Weaknesses The application does not describe the potential problems nor does it provide solutions. There is no specific description of the statistical analysis of the data. Environment:

• Environment is appropriate to conduct the study. • Relationship of project to Partnership objective and other projects • The relationship to the partnership objective is significant and appropriate. • Potential to evolve into independent/competitive project • There is significant potential for this project to evolve into another competitive project.

Weaknesses • No major weaknesses noted.

U54 Core Usage, U56/U54 This project benefitted significantly from pre-pilot funding from the U56, and from the efforts to connect Drs. Pellman and Colon-Carmona. As a result of the U56, Dr. Colon-Carmona had the opportunity to spend his sabbatical working in Dr. Pellman's lab, which enriched his science and their collaboration. Both Colon- Carmona and Pellman laboratories have an established track-record of successfully training junior scientists. The Colon-Carmona lab has trained 67 undergraduates; over half are from underrepresented minority (URM) groups. This project will utilize the 1154 Training Core to identify and recruit undergraduate students to participate in the proposed research. Undergraduate trainees will be made aware of professional development opportunities offered and will be encouraged to participate. Specifically, new undergraduate trainees will be required to participate in the research skill course early on in their research experience. PIs, post-doc and graduate student mentors will participate in the mentor training. Finally, PIs will work with the Core staff to track students and to monitor their professional development. THE FOLLOWING RESUME SECTIONS WERE PREPARED BY THE SCIENTIFIC REVIEW OFFICER TO SUMMARIZE THE OUTCOME OF DISCUSSIONS OF THE REVIEW COMMITTEE ON THE FOLLOWING ISSUES: ADDITIONAL REVIEW CRITERIA: PROTECTION OF HUMAN SUBJECTS (Resume): HS10 VERTEBRATE ANIMALS (Resume): A10 COMMITTEE BUDGET RECOMMENDATIONS: The budget was recommended as requested. BUDGET OVERLAP: None ASSESSMENT: Very Good

1 U54 CA156732-01 17 ZCA1 SRLB-3 (O1)EMMONS, K Pilot Project 2 - Racial Disparities in Depression and Mental Healthcare Utilization in Lung Cancer (Description as provided by applicant) Psychosocial problems associated with cancer care are often unaddressed, particularly related to lung cancer, which has been found to elevate risk for psychological distress relative to other cancers. Psychosocial problems can cause additional suffering, weaken adherence to prescribed treatments, and lead to increased lung cancer mortality independent of clinical factors. African American (AA) lung cancer patients may be particularly vulnerable to psychosocial problems in cancer care due to a range of issues, including access to care and other barriers. In Phase 1 of this study we will utilize a nationally representative dataset from the Cancer Care Outcomes Research & Surveillance (CanCORS) Consortium to compare prevalence of depression symptoms, factors underlying depression symptoms, and rates of mental healthcare utilization in 2108 AA and NHW lung cancer patients. We will also examine effect of cancer care experiences on depression severity at 4-months post-diagnosis. This will be the first study to conduct these analyses using a population-based approach. Data is available from patients, physicians, and medical records, and thus we will be able to test for racial disparities, adjusting for relevant demographic, medical, institutional and social/ behavioral factors. We expect to confirm some of our assumptions and generate new questions about risks and protective factors that quantitative data cannot address. Therefore, Phase 2 will include in-depth qualitative assessments of beliefs about depression and mental healthcare seeking in AA and NHW lung cancer patients at Massachusetts General Hospital. This proposed pilot project represents an innovative effort to address racial disparities in mental healthcare services, which is an understudied aspect of cancer care. The team for this mixed methods study, led by Dr. Elyse Park of DF/HCC and Dr. Sheila Cannon of UMB are well-poised to conduct this study, which will contribute significantly to their career development Both the Survey and Statistical Methods Core and Training Core will significantly contribute to this project. CRITIQUE 1: Significance: 3 Investigator(s): 4 Innovation: 4 Approach: 5 Environment: 3 1. Significance Strengths:

• The primary aim of the study is to examine possible racial disparities in depression and mental health service utilization in lung cancer patients.

• The study will be conducted in two phases: (1) utilize the Cancer Care Outcomes Research and Surveillance Consortium (CanCORS) national dataset to compare the prevalence of depressive symptoms and mental healthcare utilization among AA and NHW lung cancer patients; and (2) use in-depth individual interviews to examine the factors associated with depressive symptoms and mental healthcare seeking and see if there are racial differences in the experiences of lung cancer patients at MA General Hospital.

• The significance of the study is that there is a need to identify racial disparities in depressive symptoms in lung cancer patients. Because depression exacerbates other known risk factors for lung cancer, it is critical to identify the burden of untreated depression in lung cancer patients and racial disparities in treatment for depression in this population.

Weaknesses: • It is not clear how the theoretical framework- Self-regulatory and Explanatory models -will be

utilized in the quantitative study or to connect the two studies. If this theoretical framework is


guiding the study it would be useful to have the aspects of it that are relevant to the qualitative study or the bridging from the quantitative to the qualitative study more explicit.

• The Phase 2 aim of characterizing Phase 1 findings- (as stated in the specific aims) is unclear. The explanation offered in other sections expands the focus of this aim into several directions and it is unclear how these topics will be prioritized or followed from Phase 1. It would potentially be preferable to have the Phase 2 study test hypotheses or specific research questions generated from Phase 1 or in some other way confirm findings from Phase 1.

• There is a strong unsupported assertion that lung cancer elevates risk for psychosocial distress relative to other cancers.

• It is not simply that AA in non-cancer samples are less likely to report depression relative to NHW, it may be that they may experience less depression due, in part to behavioral coping strategies with stress such as smoking (see research by James Jackson, Harold Neighbors, Cleopatra Howard Caldwell, etc.).

2. Investigators Strengths:

• The investigative team seems well suited to conduct the proposed study, though the leadership plan is unclear.

Weaknesses: • The team seems heavily dependent on Dr. Park leading both the quantitative and qualitative

studies. • In the History and Benefits of the Partnership section, Dr. Keating is listed as a key person that

will help Dr. Park and others use the CanCORS data but Dr. Keating is not listed as one of the Co-PIs, her work is not in the preliminary studies, nor is she in the description of the overall grant application.

• Few of the investigators have used the CanCORS data or conducted and published qualitative research.

3. Innovation Strengths:

• The focus on depressive symptoms exacerbating lung cancer risk and mortality is novel. • The use of the CanCORS dataset to examine the psychological factors associated with lung

cancer in a nationally representative sample is novel. Weaknesses:

• The theoretical framework may be novel, but its use is unclear and underdeveloped. It would be preferable to have a more clear description of how the components of the framework map on to the specific aims and hypotheses in the proposed quantitative and qualitative study.

4. Approach Strengths:

• The study design and analysis plan seem adequate and appropriate for the aims. • There seems to be adequate protection of human subjects and inclusion of women and

minorities. • Recruitment for the qualitative study builds on existing studies conducted by one of the Co-Is.

Weaknesses: • The national focus of the quantitative study and the local focus of the telephone-based

qualitative study don’t seem to follow from one another. The investigators propose a phone-based qualitative interview. It is not clear why the investigators would not propose a sample of interviews that map on to the sites where the quantitative CanCORS data were collected.

• The focus of the qualitative study seems to be framed differently in each section. In some places it is described as identifying symptom presentation, mental health needs, explaining racial disparities in depressive symptoms, exploring beliefs about depression and cancer, mental health intervention preferences, etc.


• The questions for both the quantitative and qualitative studies seem quite broad. • Regression seems ok as an analytic strategy but it would have been nice to see something

more innovative or able to test more sophisticated relationships such has hierarchical linear modeling or structural equation modeling.

5. Environment Strengths:

• The environment seems quite adequate to support the proposed study. • The U54 Cores add considerable strength and expertise to the team and both the quantitative

and qualitative studies. Weaknesses:

• The limited overall experience of the team with the dataset and qualitative research. Inclusion of Women, Minorities, and Children: G1A - Both Genders, Acceptable M1A - Minority and Non-minority, Acceptable C3A - No Children Included, Acceptable Vertebrate Animals: NA Budget and Period of Support: Acceptable CRITIQUE 2: Significance: 2 Investigator(s): 1 Innovation: 2 Approach: 2 Environment: 1 1. Significance: Strengths:

• Investigation of an area of cancer-care that has traditionally received less research attention--the psychosocial health of lung cancer patients and relevant race-based mental health disparities.

• The use of a mixed methods approach to investigate race-based mental health disparities by utilizing a national database of cancer care outcomes as well as qualitative, in-depth interviews with African American and NHW cancer patients to further explore findings that emerged from the quantitative research.

• The identification of patient, provider, and system-level factors and their potential relevance to mental health disparities among African American and NHW lung cancer patients.

Weaknesses: • The research could benefit from an additional phase of quantitative research with patients from

MCH to further explore information that emerged from the qualitative research and confirm or disconfirm findings from the CanCORS database. The additional research would provide more specific information necessary for developing an intervention program with patients from MGH and strengthen the anticipated R03 intervention grant application.



• The team is comprised of investigators with complementary expertise that cover areas of qualitative research, quantitative research with large national databases, culturally informed research practices, and mental health outcomes research.

Weaknesses: No major weaknesses noted. 3. Innovation: Strengths:

• The use of a mixed methods approach to identify protective and risk factors that underlie mental health disparities in cancer.

• The use of a national database that includes information collected from patients, healthcare professionals, and medical records.



• Utilization of a national database including information from patients, providers, and medical records. The ability to examine the accuracy of patients’ self-reports mental health care utilization.

• The use of a mixed methods approach to further elucidate findings concerning mental health disparities in cancer care.

• Pilot test of the interview guide and subsequent use of feedback for revising the guide prior to implementing phase II.

Weaknesses: • Potential socio-demographic differences between MGH and CanCORS sites may make it more

difficult to tease out findings from phase 1 through qualitative interviews with MGH patients. However, the researchers indicate that additional qualitative interviews at selected CanCORS sites may also be conducted which would remedy this limitation.


• Collaboration with Dr. Pirl’s ongoing CROS study is likely to provide existing infrastructure to recruit participants for the qualitative phase of research

• Partnership with CanCORS Consortium will facilitate access and navigation of the complex dataset for quantitative analyses.

Weaknesses: No major weaknesses noted. CRITIQUE 3: Significance: 3 Investigator(s): 2 Innovation: 2 Approach: 4 Environment: 2 1. Significance: Strengths:

• The investigators have access to population database to explore the issue of depression differences among AA and NHW lung cancer patients.

• Rationale is given for higher rates of distress for lung cancer patients compared to other cancer patients; this could be tested.


• Recognition that AA patients respond differently to depression than NHW patients; further they are less likely to seek support for depression

• Researchers will examine health care utilization for mental health among the depressed lung cancer population.

Weaknesses: • Depression may be perceived differently by AA and NHW patients, making it difficult to measure

depression similarly in both groups. • AAs less likely to report depression unless it is debilitating; does that mean a skewed distribution

in AA depression? • Poor cancer care is mentioned almost as an aside; surely differences in treatment are of

paramount importance (Specific Aim 2) • Next steps are described in terms of small grants (R03s), but not an R01.


• Dr. Cannon has experience in working with AAs in research projects and can use this experience in good stead in this project.

• Dr. Cannon has an excellent career development plan. • Dr. Park has publications in qualitative research. • Dr. Pirl will assist with CanCORS analysis and with recruiting participants for Phase 2—his lung

cancer project will be invaluable. • Dr. Keating, member of CanCORS will assist in data acquisition and analysis

Weaknesses: • Dr. Cannon has limited research experience. • Dr. Traeger’s biosketch is not provided; however, he has a career development plan. • Dr. Keating’s biosketch is not included.


• Topic is highly innovative as little is known about groups’ differences in mental health status and care seeking.

• Excellent use of CanCORS dataset. • Mixed methods are likely to add depth to the quantitative data gathering. • Advance permission for publication is noteworthy.

Weaknesses: • Not clear how the two models will be used or how they will add to the work, although they

apparently were used for hypotheses generation. • The Explanatory Model and Self-Regulatory Model may be useful for the qualitative data

gathering; this was not described. • Not clear how this project will advance the field of understanding depression among lung cancer

patients. 4. Approach: Strengths:

• Excellent use of CanCORS; these data provide outstanding variables to address the questions in the Specific Aims.

• Mixed method approach is commendable. • Preliminary studies appear to be appropriate. • Good use of follow-up data to assess mental health utilization.

Weaknesses: • Not clear how this project relates to the overall U54.


• Depression inventory appears to be used on NHWs; no information is given on suitability or psychometrics for AAs.

• Adequate explanation is not provided of perceptions of cancer care as this is one of the Specific Aims—perceptions do not necessarily equate to cancer care experiences.

• Adequate information is not provided on multiple imputations. • Very little description is provided of qualitative methodology; the extraction of themes is often a

laborious process. • Recruitment may be difficult given the views of many AAs toward research; the denominator (62)

is relatively small. • The incentive payments did not appear in the budgets. • Ten interviews from each group (AAs and NHWs) is unlikely to lead to saturation for each of the

separate groups. • It is not clear what an “expert review reading of the findings” consists of.


• CanCORS is available at DF/HCC • The U54 Training Core will provide students, which is a strong feature. • The Survey and Statistical Methods Core will provide assistance. • Both institutions have strong resources.

Weaknesses: • Details on qualitative methodology are not provided. It is not clear whether qualitative methods

course exist in the environment. What services can the SSM Core provide in qualitative data analysis?

Additional Review Criteria Inclusion of Women, Minorities and Children G1A M1A C3A

• Because lung cancer rarely affects children, they are not included in this study. Vertebrate Animals NA THE FOLLOWING RESUME SECTIONS WERE PREPARED BY THE SCIENTIFIC REVIEW OFFICER TO SUMMARIZE THE OUTCOME OF DISCUSSIONS OF THE REVIEW COMMITTEE ON THE FOLLOWING ISSUES: ADDITIONAL REVIEW CRITERIA: PROTECTION OF HUMAN SUBJECTS (Resume): HS30 INCLUSION OF WOMEN PLAN (Resume): G1A INCLUSION OF MINORITIES PLAN (Resume): M1A INCLUSION OF CHILDREN PLAN (Resume): C3A VERTEBRATE ANIMALS (Resume): A10 COMMITTEE BUDGET RECOMMENDATIONS: The budget was recommended as requested.

1 U54 CA156732-01 23 ZCA1 SRLB-3 (O1)EMMONS, K BUDGET OVERLAP: None ASSESSMENT: Excellent PROJECT 1 - Latino End-of-Life Care: Patient, Provider, & Institutional Effects (Description as provided by applicant) Latinos receive more aggressive, burdensome end-of-life (EOL) care (eg, ICU stays, resuscitation) and less hospice care than non-Latino whites. The available evidence suggests that the EOL care Latinos receive may be suboptimal and inconsistent with their wishes, and inferior to the EOL care that whites receive. The overarching aim of this study is to identify the most promising targets for interventions designed to enable Latinos to receive: a) high quality EOL care, and b) care consistent with their values and preferences ("treatment goal attainment"). Our preliminary results, and those of others, suggest that there is a critical need for data at institutional, provider, and patient levels so that their relative influence can be discerned. The primary aims of the proposed study are to obtain multi-level data and use hierarchical linear modeling (HLM) to estimate patient, provider and institutional effects on Latino-white disparities in EOL care and treatment goal attainment. We hypothesize the primacy of patient and provider over institution effects, which will be significant, but less influential than either patient or provider effects. We will recruit 250 advanced gastrointestinal and thoracic cancer patients (125 Latino, 125 non-Latino white) with a life-expectancy of less than 6 months from five sites across the US. We will also enroll 50 oncology providers overall who each care for at least 5 study participants The patient's medical care received in the last month of life will be documented via medical chart extraction in the postmortem assessment. We anticipate that this study will inform policy makers and institutional leadership of where they should invest for the greatest "bang for the buck" to reduce Latino-white disparities in EOL care. The study team, comprised of Dr. Holly Prigerson, a leading expert in EOL care, and Dr. Jan Mutchler, a nationally recognized gerontologist with strong interests in disparities, is well-poised to undertake this work, in collaboration with a junior investigator at DFCI (Jimenez) and a UMB Associate Professor who wants to increase her research skills and expertise (Rivera). This project will benefit significantly from support provided by the Training and Survey and Statistical Methods Cores. CRITIQUE 1: Significance: 2 Investigator(s): 3 Innovation: 3 Approach: 5 Environment: 3 Overall Impact: Strengths:

• Prior collaborative work in the area of EOL. • Consideration of macro perspectives of EOL issues: patient, provider and institutional • Examination of health literacy as a factor in understanding EOL issues. • Strong interdisciplinary team that has previously collaborated in a productive manner. • Integration with other programs/cores, e.g., statistical core. • Attention to integration of trainees at other sites.

Weaknesses: • Conceptual underpinning of study needs further development to align goal of study, that is,

“point direction to promising targets interventions designed to enable Latinos to receive high quality EOL care” with proposed methods.


• Methodological underdevelopment and need for clarification about such aspects as: validity of tools for Spanish speaking subjects, eligibility, communication across five sites, subject interview processes and sensitivities, role of family

• Need to expand clinical discussion about expected outcomes relating to policy and institutional effects.

• Concern that the structured nature of the project may not achieve a true picture of the ‘patient’s values and preferences,” which is the main desired outcome.

• Need for justification on how idea generated and is of mutual benefit to the partners – seems one-sided toward DFCI.

Core Review Criteria: 1. Significance: Strengths:

• High quality end-of-Life for diverse populations represents a key national imperative. • Potential to offer direction for addressing EOL care at the patient and provider level.

Weaknesses: • Unclear description about how the combination of the macro approach as outlined here with

"micro" psychosocial focus of their prior EOL research informs direction for promising interventions –to increase the significance for clinical relevance.

• Potential role of the family/caregivers is unclear. 2. Investigator(s): Strengths:

• Strong study team that has previously and productively collaborated. Dr. Mutchler, UMB Department of Gerontology and Associate Director for Social and Demographic Research at the UMB Gerontology Institute, brings extensive knowledge of racial/ethnic cultural, economic, familial, and linguistic barriers to healthcare among older Latinos to study of ethnic disparities in EOL care. Dr. Prigerson (DFCI) brings extensive research expertise in EOL, and has received continual NIH support for ethnic disparities research since 2003. Her research has focused on social, cultural, and psychological determinants of medical care received near death.

• Complementary team expertise (sociology, statistics, oncology, epidemiology, demography, linguistics, psychology, nursing, theology, palliative care), all applied to the study of ethnic disparities in end-stage cancer care.

Weaknesses: • A number of trainees identified are part of the team as data collectors, data analyses. Adequate

description of the team’s communications and coordination is not provided to ensure fidelity of research processes and how trainees at MSI benefit.

• An anthropologist would enhance the team member’s expertise to provide added expertise in cultural values, beliefs and worldview.


• Focus on multi-level perspectives that capture influences at patient, provider and institutional levels that follows patients through death to determine how they affect actual EOL care received adds novelty.

Weaknesses: • Clinical impact features of the project are not well described, thus is it difficult to fully capture the

potential novelty. 4. Approach: Strengths:

• Main premise here is that the primacy of patient and provider over institution effects, which will be significant, are less influential than either patient or provider effects. Through the collection


of multi-level data and use hierarchical linear modeling (HLM), the team will estimate patient, provider and institutional effects on Latino-white disparities in EOL care and treatment goal attainment. This is a laudable goal.

• Builds on results from Coping with Cancer (CwC) study that reveals that racial/ethnic disparities in EOL care exist and prior U56 collaboration that supported collaboration between Drs. Desanto-Madeya (UMB) and Prigerson and colleagues at University of Texas to study how African-American (AA)-white cancer patient communication processes affect disparities in aggressiveness of EOL care.

• Addresses three levels: patient (e.g., provider (e.g., provider fluency) and institution) (e.g., diversity training) to offers a "macro" understanding of social forces on EOL care and uses multi-level data and hierarchical linear modeling (HLM) to estimate patient, provider and institutional effects on Latino-white disparities in EOL care and treatment goal attainment

• Support from statistical and training core is a keen strength for conducting hierarchical linear modeling (HLM).

• Involvement of trainees at other sites in the processes and methods Weaknesses:

• A key stated premise is the need to strive toward care consistent with patient’s values and preferences (treatment goal attainment). The methods proposed do not seem aligned with that goal. For example, the investigators state that aggressive medical care may run counter to traditional Latino values but how is this being considered – How do Latinos conceptualize end of life –is that known?? Will a one-time interview that entails mostly quantitative tools achieve this? Will a 5 minute interview with provider capture those salient areas? In what manner will institutional factors be fully captured across very different sites?

• Greater delineation is needed on how the proposed methods and data collected meet the overarching aim, that is, “point direction to promising targets interventions designed to enable Latinos to receive high quality EOL care.” beyond stating that the goal is to test a novel approach for generating results that would inform policy makers and institutional leadership of where they should invest for the greatest "bang for the buck" to reduce Latino-white disparities in EOL care. What does this mean? In what way can the proposed project points to promising target interventions designed to enable Latinos to receive high quality EOL care?

• Unclear how the idea emanated as a priority research foci from both partners – this is uncertain and not well justified.

• No mention of family perspectives considering the nature of the topic. • Selection of sites is ‘strategically planned’ but rationale is unclear about this selection. • Regarding surveys and tools: Discussion of reliability and validity of some of the tools for

Spanish speakers, e.g., treatment attainment, therapeutic alliance, religious, coping, knowledge of risks/benefits (TACT scale) tested on Blacks – Have all tools been validated among Latinos? In what manner were the instruments created and how were the domains of interest identified by the team

• Concern for participant burden – have tools been pretested for ease of administration, subject burden and understanding?

• Health literacy is suggested as an influencing predicting factor of EOL decisions (understanding), which is an interesting element of the study: some discussion is warranted on the reliability and validity of the REALM SF for Spanish speakers?


• Cancer center and community resources strongly support the successful implementation of this program.

Weaknesses: • Description of data collection sites (5) are scant – e.g., research infrastructure, data collection

processes is not clear.

1 U54 CA156732-01 26 ZCA1 SRLB-3 (O1)EMMONS, K Additional Review Criteria Protections for Human Subjects: Unacceptable

• Added details about the subject interview procedures are needed to ensure protections. For example, subjects are asked about their prognostic acceptance of terminal illness on a scale that spans: relatively healthy, relatively healthy but terminally ill, seriously but not terminally, seriously ill and terminally ill. In consideration that a prior pilot showed that 50% of subjects were not aware that their disease was incurable, how is this communication going to be handled and what are referral processes/resources available at each of the five sites.

Inclusion of Women, Minorities and Children G1A M1A C3A CRITIQUE 2: Significance: 1 Investigator(s): 1 Innovation: 2 Approach: 5 Environment: 3 Core Review Criteria: 1. Significance: Strengths:

• This is a critical issue to address in Latino health delivery disparity. Data to date show that Latinos receive excessive intensity of EOL care in spite of their preference for less intense care. Multiple reasons appear to be responsible for this, but their relative contributions are not clear.

• This study will allow the first careful analysis of the relative contributions of patient, provider and institution to the problem.

• The results promise strong potential for clear policy implications. • This study extends the collaboration into the psychosocial and health systems aspects of cancer

disparities. Weaknesses:

• Methodological concerns may confound the results and make identifying policy implications more difficult.


• Four PIs collaborate: • Dr. Prigerson from DFCI has had prior R01 funding related to this question; has had continuous

NIH funding since 2003. • Dr. Macijiewski from DFCI is an experienced statistician and collaborator on Prigerson team. • Dr. Mutchler, cultural sociologist from UMB contributes to the depth of cultural understanding

involved in the study design and in drawing conclusions from the study • Dr. Rivera from UMB has received federal funding to study healthcare literacy in Latino health;

her role as Director of the UMB Latino Leadership Opportunity Program will help guide young Latinos into study research positions and provide them training in research methodology.

• Investigators bring strong and complementary methodological skills and history to the project


• Team members from distant sites (e.g. Paulk from Texas, Munoz from California) bring distinctive backgrounds as well with Paul from oncology and Munoz a minister who is completing his PhD in Psychology while working as Head Chaplain at the California site.

Weaknesses: • Perhaps greatest concern is that Rev. Munoz may be doing so much family discussion that the

California site may not reflect the normal course of clinical care and discussions during terminal care for Latinos of Mexican background

• It may be difficult to separate his influence from the site from other factors involved. • The investigators attempt to control this methodologically or statistically but appropriate details

are not provided. 3. Innovation: Strengths:

• Design: By measuring data at the patient, provider and treatment site level, it may be possible to determine most likely impact points for proposed policy changes.

• Designed to identify targets for policy change that should lead to the possibility of measuring impact of interventions on decreasing the discrepancy between Latino stated desires for end of life care with actual experience.

• Using many measures that have been validated by investigators and have a track record of utility in this research

• Converting to money metric to allow intensity of EOL care to be quantified on a continuous basis • Using a variety of measures of target of project: patient preferences, acculturation, • Measures have been translated to Spanish • Measures have published validation in English forms

Weaknesses: • Psychometric properties of Spanish versions of measures are not cited. • Not stated if a single monetary standard for care events will be used; if only a total dollar cost of

care is provided, this may be confounded by costs of care in the three disparate geographic regions and the multiple hospital systems involved.

• If the California results differ from the Texas and Massachusetts results, it may be a confound of the strong participation of Rev. Munoz in counseling patients as Chief Chaplain.


• Study appears adequately powered • There has been a history of conducting related research with related variables over time. • Three sites will provide patients. • Researchers on the ground will be trained across sites to provide some procedural validation • Patients recruited and interviewed in last six months of life. • Costs of care to be calculated posthumously for last 30 days of life as measure of intensity of

care (this provides a continuous measure which enhances the statistical capacity of the study). Weaknesses:

• Boston site is more likely to have predominantly Puerto Rican patients; Latinos from Mexican heritage are more likely to comprise the patients in Texas and California (also different cultures)

• No mention is made of consideration of GEE modeling to control for the nesting of patients within providers within settings.


• DFCI is a strong and robust research environment. • The team has collaborated on prior published research on related questions. • The measures have been used successfully.


• Three sites in different parts of country enhance chance of increasing robustness of sampling Weaknesses:

• One site has a bilingual minister (studying for his doctorate in psychology) running the study at that site; he could singlehandedly make the data from this site very different from the other two sites

Additional Review Criteria Protections for Human Subjects:

• The investigators state that up to 50% of terminally ill Hispanic patients are not aware that they are terminally ill. Thus, some patients are likely to become aware that they are terminally ill in the process of this study. There needs to be assurance that counseling is available for distressed patients and family members at each site when this occurs.

Data and Safety Monitoring Plan (Applicable for Clinical Trials Only):

• Patients are under medical care at these sites for their cancer. The study will not interfere with their ongoing cancer care.

Inclusion of Women, Minorities and Children When the proposed project involves clinical research, the committee will evaluate the proposed plans for inclusion of minorities and members of both genders, as well as the inclusion of children.

• Children will not be Vertebrate Animals

• Not applicable. CRITIQUE 3: Significance: 1 Investigator(s): 2 Innovation: 1 Approach: 5 Environment: 2 Core Review Criteria: 1. Significance: Strengths:

• The primary aim of the study is to conduct a quantitative study that examines patient, provider and institutional effects on Latino-White disparities in EOL care and treatment goal attainment.

• The study endeavors to estimate and essentially rank the effects of patient, provider and institutional factors on Latino-White disparities in EOL care and treatment goal attainment. The literature to date has not tested the independent and additive effects of these factors empirically and simultaneously.

• This topic seems to be an important focus of NIH, and these disparities have rarely been studied in the context of Latino-White disparities.

Weaknesses: • The review of the literature focused almost exclusively on the work of the investigators. There is

no mention of other work in the scientific literature, even that which focuses on other racial/ ethnic disparities.



• The research team seems extremely well positioned to conduct the proposed study. They have individual and complementary expertise and experience working together.

Weaknesses: • No major weaknesses are noted.


• This project tests the assertion that Latino-White disparities in EOL care are driven by institutional factors and hypothesizes that they are more driven by patient and provider factors.

• As opposed to studying hypothetical situations, this study actually follows patients through death to determine the level of congruence between the patient’s wishes and the EOL care received. This strategy also allows the researchers to do cost analyses to assess the aggressiveness of care.

• Including sites in the MA, TX and CA is novel and adds breadth to the study. • The primary focus on Mexican Americans also is novel.

Weaknesses: • Because institutional influences work through patient and provider factors, it seems clear that all

three are relevant. While statistically one can control for these factors, what is less clear is conceptually how the investigators disentangle these factors. Ethnicity of the patient occurs in the context of his/ her intrapersonal characteristics, the patient-provider interaction, and the institutional, community and regional context. It may be that the social psychological focus of the study will lead the investigators to identify social psychological factors. Conversely, an organizational or institutional theory may help to identify key factors that may be at play and interact with ethnicity at higher levels than the individual patient or the patient-provider interaction.


• The study seems congruent with the literature and well designed. • The analysis plan also seems well developed and adequate.

Weaknesses:

• It is not clear how the approach will test the relative importance of organizational/ institutional factors.

• There is no explicit timeline for the proposed study and its various components. 5. Environment: Strengths:

• The investigative team is outstanding and the lead investigators have worked together on several previous studies.

• How the team plans to utilize the center resources to support and enhance this intervention also is impressive and maximizes the resources of the proposed center.

• The universities and institutional support are certainly adequate and build on the collaborative relationships of the investigators.

Weaknesses: • Investigator with explicit interest and expertise in institutional factors is not identified to develop

and test this component of the study. THE FOLLOWING RESUME SECTIONS WERE PREPARED BY THE SCIENTIFIC REVIEW OFFICER TO SUMMARIZE THE OUTCOME OF DISCUSSIONS OF THE REVIEW COMMITTEE ON THE FOLLOWING ISSUES:

1 U54 CA156732-01 30 ZCA1 SRLB-3 (O1)EMMONS, K Additional Review Criteria: PROTECTION OF HUMAN SUBJECTS (Resume): HS44 Unacceptable Added details about the subject interview procedures are needed to ensure protections. For example, subjects are asked about their prognostic acceptance of terminal illness on a scale that spans: relatively healthy, relatively healthy but terminally ill, seriously but not terminally, seriously ill and terminally ill. In consideration that a prior pilot showed that 50% of subjects were not aware that their disease was incurable, how is this communication going to be handled and what are referral processes/resources available at each of the five sites. INCLUSION OF WOMEN PLAN (Resume): G1A INCLUSION OF MINORITIES PLAN (Resume): M1A INCLUSION OF CHILDREN PLAN (Resume): C3A VERTEBRATE ANIMALS (Resume): A10 COMMITTEE BUDGET RECOMMENDATIONS: The budget was recommended as requested. BUDGET OVERLAP: None ASSESSMENT: Very Good PROJECT 2 - In vivo analysis of signaling dynamics in the Notch interaction network (Description as provided by applicant) The Notch signaling pathway plays a critical role in multiple cell fate decision events in metazoans, and recently has been implicated in the pathology of cancer in humans. Genetic and biochemical evidence has revealed a large network of modulators that are involved in establishing a precise level of Notch signaling and determining tissue-specific outcomes of pathway activation, from the interaction of the Notch receptor with its ligands Delta and Serrate to transcriptional regulation of the Notch target genes. Though much of this knowledge has been obtained using Drosophila as a model organism, it is relevant for understanding Notch function in humans due to a remarkable conservation of the fundamental steps in Notch signaling between flies and mammals. Yet, a major obstacle has been an inability to study endogenous signaling events. In this study, we propose to gain insight into the Notch signaling events by using the genetic advances in recombineering and targeted transgene insertions to replace the endogenous Notch and Delta genes with their fluorescent and affinity tagged isoforms. These transgenes will be used for studying the composition of Notch containing signaling complexes and for imaging the process of Notch activation in vivo. Completion of these experiments will establish an in vivo map of the Notch interaction network and reveal the dynamics of signaling in living cells. With the above in mind, we will pursue the following specific aims: 1) To generate Drosophila lines containing genomically tagged Notch and Delta, 2) To analyze the Notch interaction network in vivo, and 3) To study the dynamics of Notch signaling in vivo. Moreover, this collaboration will have multiple benefits for the continued professional development of Dr. Veraksa's career. While the two principle investigators have a history of productive collaboration. Dr. Veraksa is early in his career as an independent investigator; yet both Veraksa and Artavanis-Tsakonas bring complementary expertise to the proposed project. This collaboration will also significantly benefit from the Training Core. CRITIQUE 1: Significance: 2 Investigator(s): 1

1 U54 CA156732-01 31 ZCA1 SRLB-3 (O1)EMMONS, K Innovation: 2 Approach: 4 Environment: 1 1. Significance: Strengths:

• Targeting the Notch pathway is recognized as an important goal for cancer therapeutic development.

• A further understanding of the Notch pathway with its cross-talk with other pathways will be important for designing the rational use of Notch inhibitors with other targeted agents.

Weaknesses: • The investigators point out that the methods that they will use to produce the transgenic

Drosophila lines were originally developed for manipulating mammalian genes, so they could have chosen human cancer cell lines for their model. They point out good reasons for the use of Drosophila including the lack of redundancy which complicates experiments in mammal model systems. However they don’t specifically state the redundancy that occurs with Notch and Delta. Furthermore drawbacks of the Drosophila model aren’t considered such as the inability to study this pathway in malignancy. However, this is a minor criticism as using the Drosophila model will likely produce insight into the basic biology of this pathway which could subsequently be applied to human malignancy.


• Both investigators are fully capable of conducting the work described. Weaknesses:

• The MSI investigator was formerly a post-doc in the Cancer Center investigator’s laboratory, raising the question of independence. However this is a very minor concern.

3. Innovation: Strengths: The approach of using recombineering to replace the Notch and Delta genes in the genome with tagged genes in the genome is very innovative, potentially resulting in powerful tools to study the Notch pathway.

• The ability to image the transgene products in vivo with FL-tagged proteins and confocal microscopy is very innovative.

• There is a high likelihood that the investigators will discover new aspects of the Notch pathway. Weaknesses: No major weaknesses noted. 4. Approach: Strengths:

• The approach is extremely well designed, with a logical and comprehensive progression of experiments.

• The methodology for isolation of protein complexes (single-step SBP-based purification) and identification using mass spec is very powerful.

• The transgenic lines that they intend to produce will be very powerful tools. • The preliminary data presented provide confidence that they are fully capable of performing the

work described. Weaknesses:

• Specific Aims 2 and 3 depend completely on the success of Aim 1, which involves the generation of the various Notch and Delta transgenic lines containing GFP or SBP tags in intracellular and


extracellular domains of the proteins. If they are not successful in generating the transgenics, the bulk of the work proposed won’t be able to be done.

• In preliminary data the investigators have demonstrated their ability to make a transgenic line using un-tagged Notch, and they have constructed the SBP-Notch transgene construct that is functional in S2 cells, but have not yet demonstrated that they can successfully produce tagged-gene transgenic lines.

• The tags could possibly interfere with the function of the expressed transgene products, or alter it ability to serve as a substrate for proteases or ubiquination. The investigators did show that other GS-TAP- tagged proteins were functional in vivo and the proposed SBP tag is a subunit of the GS-TAP tag which provides some assurance that the proposed transgene products will be functional. However there is some concern that a GFP-Notch cDNA product could only partially rescue Notch mutants.

• It is convincing that their methods are sensitive enough to study protein complexes that can be isolated from entire organisms; however there is concern that the more relevant experiments in specific organs may not yield sufficient protein. Can sufficient amounts of tagged-protein complexes be isolated from wing discs of larvae? The feasibility of these needs to be discussed.


• Exceptional. Weaknesses: No major weaknesses noted. CRITIQUE 2: Significance: 4 Investigator(s): 2 Innovation: 2 Approach: 3 Environment: 2 1. Significance The proposed project is significant due to the approach to understand modulators of the Notch signaling pathway, its activation and the interaction of the Notch receptor with its ligands Delta and Serrate in cancer etiology. Deregulation of this highly tight controlled pathway is known to play a role in a number of human pathologies, including cancer. Activated mutations in the Notch 1 receptor has been found in over 50% of human T cell acute lymphoblastic leukemias, and other cancers such as lung, breast and cervical cancers. The Notch pathway, along with Wnt, is important in stem cell maintenance and has been implicated in the switching of normal cells to cancer cells. Although the Drosophila has been the model of choice for studying the Notch pathway, technical limitations have prevented it use in investigating the endogenous signaling events. Genetic advances in recombineering and targeted integration to replace endogenous Notch and Delta genes with fluorescently and affinity tagged isoforms, will allow in vivo observation of Notch signaling in live cells. This proposal addresses an important barrier to understanding modulators of endogenous Notch and Delta genes in cancer or stem cells involvement in cancer. Strengths:

• Complementary expertise of the two investigators is a strength. • Preliminary data presented further strengthen the success of this research.

2. Investigators Dr. Veraksa is highly trained in this research field through the pilot project funded by the previous U56 grant and her post-doctoral training. She was post-doc in the Artavanis-Tsakonas laboratory. Dr. Artavanis-Tsakonas is a renowned expert in the field of Notch signaling.

1 U54 CA156732-01 33 ZCA1 SRLB-3 (O1)EMMONS, K 3. Innovation The proposed model of using the tagged Notch and Delta proteins expressed in their native genomic context is innovative. Development of new gene manipulation techniques has allowed the model to be use to investigate endogenous activation of both Notch and Delta proteins in the Drosophila. 4. Approach Preliminary results suggest that their approach has high potential for success of their project. 5. Environment The environment at UMB and Dana Faber/Harvard Cancer Center are suitable for the proposed research. CRITIQUE 3: Significance: 2 Investigator(s): 2 Innovation: 4 Approach: 2 Environment: 2 1. Significance: Strengths:

• The project – to tag the genomic copies of the Notch and Delta, and then exploit strains containing those tagged genes – will provide important tools for analysis of the Notch system in Drosophila. Since this system has historically been a critical platform for studies of this developmentally central and evolutionarily conserved signaling system, these tools are likely to be powerful additions to the field.

• The affinity-tagged genes are designed for biochemical applications, and the purification procedures developed by the applicants are likely to facilitate such applications in a variety of contexts.

• The fluorescent derivatives are similarly powerful for cell biological applications, and the choice of tags will make them versatile.

• The phiC31 integrase system permits the generation of strains which will allow combination of these tagged genes with other gene modifications, making them quite general.

• If generated, the modified genomic genes will be subject to the normal regulation and expression patterns that are characteristic of the untagged genes.

Weaknesses: • One weakness of the approach is inevitable –tagging genes always runs the risk of altering the

behavior of the gene product at the biochemical and cell biological level. The investigators include several tests of the genetic competence of the tagged genes, but whether the observed biochemical and cell biological behavior is largely normal is difficult to ascertain.

• A second weakness is that the connection to Notch involvement in cancer outcomes is, at best, uncertain. While it is true the system would allow examination of the phenotype in Drosophila of mutations known to result in oncogenic phenotypes in humans, it is not at all clear that the secondary interactions which underlie the human phenotypes will be reproduced in the insect system – the basic signaling mechanism is highly conserved, but that conservation is likely to weaken as the components at issue are further removed from the central axis.



• The investigators have worked together in a productive relationship for several years, with good reason to think they can continue.

• Prof. Veraksa has established an independent set of competencies and an active independent training program at UMB.

• Prof. Artavanis-Tsakonas is a senior, well-established investigator in the Notch field, whose resources in expertise, experience, and reagents are extensive and pertinent.



• Although the phiC31 system was published a couple of years ago, its application to this particular system will be useful and reap potential dividends in the future.

• The compaction of the TAP purification system to a single-step purification, if it proves efficient in a variety of contexts, is an excellent innovation, and is particularly useful in the context of training graduates students and undergraduates, because it is likely to make it possible for novices to reach productive results in a plausible time.

Weaknesses: • The primary advantage of the system is the technically elegant and rigorous approach to the

expression of modified genes. But there are no clear examples of situations or results where this elegance and rigor is necessary to improve our understanding.

• Related to the last point, these methods are likely to be relatively slow, and in the absence of situations where cDNA-based methods clearly give rise to suspicious results, these experiments may often be relegated to confirmatory status.


• The strength of this approach is that key technical requirements for the project (transgene constructions, protein purifications) are all in place and have been subjected to at least preliminary testing.

• The third technical requirement – confocal visualization of tagged gene products – is not particularly problematic; it is subject primarily to equipment and experience limitations, both of which are not a problem in this environment.

Weaknesses: • In the protein purification (Aim 2), steps have been taken to minimize the possibility that the

introduction of the 4 kB SRP will alter interaction patterns, but there is no obvious way to test whether these steps have been effective.

• In the protein purification (Aim 2), the reduction of expression levels to endogenous values puts stress on the ability to recover analyzable amounts of protein. The simplification of the purification protocol is meant to address this problem, but whether it will make the experiments feasible with reasonable amounts of tissue other than whole eggs and larva is difficult to say.

• In the protein localization (Aim 3), there are claims of preliminary evidence for normal localization of proteins tagged as planned in the proposal – it is difficult to determine how convincing these preliminary results might have been.

• In the protein localization (Aim 3), there is an intention to follow trafficking by real-time imaging of single vesicles. However, the system is designed to produce low-level (physiological) expression levels, and the ability to maintain long-term observations may be limited by bleaching of an (intentionally) weak signal.


• The basic environments at both institutions are adequate in terms of equipment and other resources.


• The primary relationship of this project to the overall program is in its training implications, particularly at UMB. The exposure of graduate and undergraduates both to the techniques and to the partner operation at DFHCC will be valuable regardless of final scientific impact of the work.

Weaknesses: • There is little or nothing in this project that addresses cancer or cancer disparity issues, by its

nature. THE FOLLOWING RESUME SECTIONS WERE PREPARED BY THE SCIENTIFIC REVIEW OFFICER TO SUMMARIZE THE OUTCOME OF DISCUSSIONS OF THE REVIEW COMMITTEE ON THE FOLLOWING ISSUES: ADDITIONAL REVIEW CRITERIA: PROTECTION OF HUMAN SUBJECTS (Resume): HS10 VERTEBRATE ANIMALS (Resume): A10 COMMITTEE BUDGET RECOMMENDATIONS: The budget was recommended as requested. BUDGETARY OVERLAP: None ASSESSMENT: Outstanding PROJECT 3 - Covalent Fluorescent Probes for Cancer Cell Detection (Description as provided by applicant) Fluorescence imaging is a powerful tool that permits visualization of specific cell states within a population; however, existing methods for fluorescence labeling are not experimentally accessible for many biological systems. Furthermore, fluorescent small-molecule sensors of cell state may provide a valuable alternative with significant benefits relative to existing methods for fluorescence imaging. The overall goal of this project is to create fluorescent small molecule ATP-site directed probes that can selectively label particular kinases and serve as imaging probes of normal versus pathological cell state. Protein kinases are in many ways ideal targets for the development of selective small molecule imaging probes for use in cancer biology. This is because protein kinases are involved in most cellular processes and changes in their localization, accessibility, and abundance are associated with changes in cellular state. Protein kinases have been used as biomarkers in cancer biology because the loss of endogenous kinase regulatory mechanisms by point mutations, gene deletions, gene amplifications, and chromosomal rearrangements has been well-established as crucial events in many cancers. The specific aims of this project are to: 1) Synthesize fluorescently-tagged kinase inhibitors capable of forming covalent bonds with ATP-site cysteine residues; 2) Use microscopy-based screening of the compounds prepared in Aim 1 to identify compounds that are selective-probes of normal and pathological cellular states and 3) Identify the intracellular target(s) of active compounds identified in Aim 2. This proposed is the extension of an ongoing collaboration between Drs. Nathanael Gray (Dana Farber Cancer Institute), Priscilla Yang (Harvard Medical School) and Wei Zhang (UMass Boston). All three are also members of the Dana Farber/Harvard Cancer Center. One of the strong points of this proposal is that each Co-Pl is responsible for one of the three Specific Aims allowing the project to be benefited by the balanced skills and expertise that each person and their subsequent institution brings to the partnership. Because all three investigators are early in their careers, Drs. Gray, Yang and Zhang will benefit from career development activities and mentors who are internal and extrnal. Additionally, the Training Core will significantly contribute to this project.

1 U54 CA156732-01 36 ZCA1 SRLB-3 (O1)EMMONS, K CRITIQUE 1: Significance: 3 Investigator(s): 2 Innovation: 2 Approach: 4 Environment: 1 1. Significance: Strengths:

• The availability of specific small molecule florescent probes that specifically bind to proteins that are aberrant in cancer cells could be very useful in studying the biology of the target proteins.

Weaknesses: • Other methods already exist that serve the same purpose as the proposed probes, which are in

the “monitoring of intracellular kinase abundance and localization” (eg monoclonal antibodies). The investigators argue that the proposed small molecule probes have advantages over antibodies, such as the ability to use the small molecules in live cells. However they fail to point out that there are disadvantages as well. The specificity of antibodies is far greater than small molecules which can often bind to multiple targets which is a very significant concern.


• All of the investigators appear to have the expertise to carry out the proposed work. Weaknesses:


• Using small molecule inhibitors linked to fluorescent molecules that can covalently bind to the target kinase as a tool for studying the kinase in cells is highly innovative.

• The production of libraries of fluorescently tagged small molecule kinase inhibitors is innovative. Weaknesses:

• The work proposed is essentially to generate and validate reagents. 4. Approach: Strengths:

• The chemistry described is a clear strength. • The validation plans are sound.

Weaknesses: • The ability to perform the work described in Specific Aims 2 and 3 will hinge on the success of

Aim 1. In preliminary experiments the investigators were able to covalently label EGFR kinase with a fluorescent small molecule inhibitor (WZ4002), however, they failed to present evidence that this probe could be used for its intended purpose- to visualize the EGFR in intact cells. Therefore the preliminary data are not sufficiently convincing that they can produce the probes that will be necessary to accomplish Aims 2 and 3.

• In general pitfalls and alternative strategies are not discussed. • Specific Aim 1 will be done at the MSI, whereas Aims 2 and 3 will be done at DFCI and the

Harvard Medical School. According to the RFA: “Joint research projects conducted primarily at the Cancer Center must specifically address areas of cancer disparity in racial and ethnic minority and socio-economically disadvantaged populations.” More than half of the work proposed will not be done at the MSI.

1 U54 CA156732-01 37 ZCA1 SRLB-3 (O1)EMMONS, K 5. Environment: Strengths:

• Both institutions have exceptional environments to perform the work proposed. Weaknesses:

• No major weaknesses noted. CRITIQUE 2: Significance: 3 Investigator(s): 2 Innovation: 3 Approach: 3 Environment: 3 Dana Farber Cancer Institute, Harvard Medical School, and U. Mass Boston are co-leading sites for this basic science project. This team of investigators received pilot project support in year 4 of the U56. The submitted project builds upon this initial work. Dr. Zhang's lab will develop fluorescently-tagged kinase inhibitors using both a targeted and library approach. Microscopy-based screening of the compounds produced by Dr. Zhang's group will be validated for selectivity in detecting "transformed" verses "normal" cell lines by Dr Yang and Gray. Finally, the team will identify the intracellular targets of active compounds using a panel of known kinases as well as using affinity chromoatograpy- mass spectrometry-based approaches. Summary: Fluorescence imaging is a powerful tool that permits visualization of specific cell states within a population; however, existing methods for fluorescence labeling are not experimentally accessible for many biological systems. Furthermore, fluorescent small-molecule sensors of cell state may provide a valuable alternative with significant benefits relative to existing methods for fluorescence imaging. The overall goal of this project is to create fluorescent small molecule ATP-site directed probes that can selectively label particular kinases and serve as imaging probes of normal versus pathological cell state. Protein kinases are in many ways ideal targets for the development of selective small molecule imaging probes for use in cancer biology. This is because protein kinases are involved in most cellular processes and changes in their localization, accessibility, and abundance are associated with changes in cellular state. Protein kinases have been used as biomarkers in cancer biology because the loss of endogenous kinase regulatory mechanisms by point mutations, gene deletions, gene amplifications, and chromosomal rearrangements has been well-established as crucial events in many cancers. The specific aims of this project are to: 1) Synthesize fluorescently-tagged kinase inhibitors capable of forming covalent bonds with ATP-site cysteine residues; 2) Use microscopy-based screening ofthe compounds prepared in Aim 1 to identify compounds that are selective-probes of normal and pathological cellular states and 3) Identify the intracellular target(s) of active compounds identified in Aim 2. This proposed is the extension of an ongoing collaboration between Drs. Nathanael Gray (Dana Farber Cancer Institute), Priscilla Yang (Harvard Medical School) and Wei Zhang (UMass Boston). All three are also members of the Dana Farber/Harvard Cancer Center. One of the strong points of this proposal is that each Co-Pl is responsible for one of the three Specific Aims allowing the project to be benefited by the balanced skills and expertise that each person and their subsequent institution brings to the partnership. Because all three investigators are early in their careers, Drs. Gray, Yang and Zhang will benefit from career development activities and mentors who are internal and external. Additionally, the Training Core will significantly contribute to this project. 1. Significance:

1 U54 CA156732-01 38 ZCA1 SRLB-3 (O1)EMMONS, K Fluorescent small-molecule sensors of cell state may provide a valuable alternative with significant benefits relative to existing methods for fluorescence imaging. Protein kinases are in many ways ideal targets for the development of selective small molecule imaging probes for use in cancer biology. This is because protein kinases are involved in most cellular processes and changes in their localization, accessibility, and abundance are associated with changes in cellular state. Protein kinases have been used as biomarkers in cancer biology because the loss of endogenous kinase regulatory mechanisms by point mutations, gene deletions, gene amplifications, and chromosomal rearrangements has been well-established as a crucial event in many cancers. 2. Innovations: Fluorescent small-molecule sensors of cell state may provide a valuable alternative with significant benefits relative to existing methods for fluorescence imaging (Table 1). First, due to their low molecular weight relative to antibody reagents, small-molecule probes are more likely to be cell permeable, a property that can permit their use in live cell and in vivo imaging and that may simplify their use in the imaging of fixed samples. In addition, their small size makes them less likely than large protein tags to disrupt the structure and/or function of the cellular species to which they bind; consequently, they are more likely to be phenotypically benign. 3. Investigators: Both investigators are well published and experienced researchers in this area. They have a previously established working relationship and have demonstrated productivity. 4. Approach: The goal of this project is to create fluorescent small molecule ATP-site directed probes that can selectively label particular kinases and serve as imaging probes of normal versus pathological cell state. The approach is clearly described. The application does not discuss potential problems and therefore does not discuss solutions. 5. Environment The environment is appropriate to conduct the project. U54 CORE USAGE AND VALUE ADDED FROM THE U56/U54 This project benefitted significantly from the U56 in terms of identifying the potential for collaboration, and nurturing it through pilot grant support. The Training Core will be utilized to support the UMB students participating in the project and for student recruitment services. Over three years of the grant period, the Zhang group expects to have up to 10 undergraduate students performing senior thesis research (1 year project) or summer research (2-3 months projects), and 4-5 graduate students, most of whom will be under-represented minority (URM) students who might otherwise not be aware of the research opportunities afforded to this project The Training Core will also facilitate UMass students ability to visit and perform experiments in the (3ray and Yang labs at DF/HCC. This will allow exposure to general biological techniques, microscopy, and biochemistry. The Zhang group will work with the Training Core to develop Research Skill modules that students will take prior to beginning the research internship to have students well prepared as they enter into their respective research environment. Training Core sponsored activities will also provide student trainees with helpful information for career development. The URM undergraduate students will be encouraged to pursue graduate studies in different areas of life sciences. The PIs will also provide names and contact information of all trainees affiliated with the proposed project to ensure outcomes are monitored and will encourage students to participate in follow up surveys and studies. CRITIQUE 3: Significance: 3 Investigator(s): 2 Innovation: 4

1 U54 CA156732-01 39 ZCA1 SRLB-3 (O1)EMMONS, K Approach: 4 Environment: 3 1. Significance: Strengths:

• The investigators seek to unite a platform for identifying drug sensitivities in cancer cells with the development of new small molecule inhibitors of kinases that carry fluorescent or affinity groups along with –SH reactive moieties . Such molecules would have both diagnostic and even potential therapeutic implications.

• Because the aim is to test new compounds in a fairly broad based screen, the method has the potential to uncover unexpected targets.

Weaknesses: • The most significant outcomes of these experiments are quite far downstream and depend on

successes at the screening step that are uncertain. • It is not clear how well the cell line collection will serve as a platform for a screen of molecules of

unknown properties – characterization of the collection has been primarily at the level of molecules with known specificities (although some proposed specificities did not survive testing in the system).


• The expertise of the synthetic organic chemists (Gray and Zhang) makes it likely that the combinatorial chemistry will be successful.

• Prof Yang has had experience with a related cell-based screen for phenotype-specific fluorescent small molecule probes.

Weaknesses: • The primary expertise in kinase inhibitor synthesis seems to reside in the Gray laboratory, but

the primary responsibility for synthesis resides in the Zhang laboratory. • The Gray laboratory is responsible for the affinity purification of kinase targets, for which the

laboratory does not seem to have any particular expertise (the three references from graduate student days notwithstanding).


• The synthesis of several components (diversity site synthesis of kinase inhibitors, cell line collection of oncogenic phenotypes, screening of fluorescent probes for phenotype-specific interactions) is novel.

• The use of the cell line collection as a screening platform is a good extension of the published work on interaction of inhibitors of known specificity with (a subset?) of those lines.

Weaknesses: • Oddly, the applicants repeatedly wander away from the novel thread to mop-up experiments with

previously designed inhibitors that properly belong in other projects, but are presented here under the guise of “controls”. For example, Specific Aim 2 begins with characterization of the interaction of previously synthesized (and chemically unrelated) BODIPY-labeled inhibitors with cell lines in which the known targets of the inhibitors are over-expressed. These are indeed interesting experiments, but even if successful, they provide little information about the likely usefulness of Dr. Settleman’s cell line panel in distinguishing between characteristics of closely related pyrimido-diazepinone compounds.

• The incorporation of irreversibility into the objectives of probe design means that probes can be trapped in the active sites of kinases for which they have relatively weak noncovalent specificity. The relative contributions to the fluorescence signal, mass spectrometric patterns, and eventually phenotypic effects will depend on details of exposure – concentrations, times, buffer conditions, etc.

1 U54 CA156732-01 40 ZCA1 SRLB-3 (O1)EMMONS, K 4. Approach: Strengths:

• The combination of the fluorous capture and kinase inhibitor library synthesis scheme provide a promising approach to synthesis of a diverse range of compounds.

• The basic screening procedure is capable of generating interpretable patterns of staining for any compound with a substantial differential affinity for a particular kinase.

• It is possible that the affinity tag (substituted for the BODIPY group) will provide an avenue for purification of those proteins to which any given probe binds

Weaknesses: • The investigators suggest that known protein structures and modeling will inform these

experiments, but there is little evidence that they have done so. For example, the text (but not Fig 8) suggests that the BODIPY (and by extension, the affinity tag) can be attached to any of the diversity sites, when in fact structural evidence suggests that only R1 will be suitable for that purpose.

• Similarly, the location of potential –SH targets for the acrylamide moiety is not discussed, although structural and sequence evidence would permit sensible statements on this subject.

• If the screening protocol does give rise to distinct staining patterns for any given derivative, the problem of identifying the target is a difficult one. The kinome assays are relatively straightforward, but there is no reason or evidence to suggest that those assays will yield an unambiguous indication of the potential targets.

• The complementary affinity purification approach is more direct that the Xenopus assays described in the references (Rosania et al), but is unvalidated by preliminary experiments.


• The combination of two synthetic laboratories offers an interesting, challenging, and potentially productive environment for the synthetic chemistry aspects of the project.

• The experience of the Yang laboratory screening for compounds that specifically stain virally infected cells is valuable experience for the second aim.

• The potential identification of probes that can characterize particular oncogenic alterations in primary cells or clinical isolates is a strong asset in the overall program.

Weaknesses: • It is not clear that there is sufficient expertise to support the affinity purification validation of

potential targets. • The training aspects of this project are difficult to discern, since the modules are quite separate,

and it is not clear how interactions between the institutions will be encouraged. THE FOLLOWING RESUME SECTIONS WERE PREPARED BY THE SCIENTIFIC REVIEW OFFICER TO SUMMARIZE THE OUTCOME OF DISCUSSIONS OF THE REVIEW COMMITTEE ON THE FOLLOWING ISSUES: ADDITIONAL REVIEW CRITERIA: PROTECTION OF HUMAN SUBJECTS (Resume): HS10 VERTEBRATE ANIMALS (Resume): A10 COMMITTEE BUDGET RECOMMENDATIONS: The budget was recommended as requested. BUDGET OVERLAP: None

1 U54 CA156732-01 41 ZCA1 SRLB-3 (O1)EMMONS, K ASSESSMENT: Excellent PROJECT 4 - Nursing Post-Doctoral Program in Cancer and Health Disparities (Description as provided by applicant) The Nursing Post-Doctoral Program in Cancer and Health Disparities is designed to address the urgent need for more minority and non-minority nurse researchers prepared to teach at the university level and conduct independent nursing research. Through the U56, we have developed and implemented an Accelerated BSN-to-PhD Program, and a post-master's certificate R25 training program in oncology (currently under review). The proposed Post-Doctoral Program leverages the resources and strengths of this partnership to develop and implement a nationally recognized post-doctoral research training program, designed to ensure a diverse and highly trained workforce to meet the nation's need for nursing faculty and researchers committed to understanding and addressing cancer health disparities. The Program will have three interrelated components: (1) an educational training component in which trainees are supported in designing an individualized curriculum that addresses gaps in their nursing PhD training and supports them in acquiring skills and knowledge required to conduct independent research in nursing and cancer health disparities; (2) a research training component in which trainees will conduct a mentored research project in cancer health disparities; and (3) professional development training that will provide trainees with support and resources required to develop a research career plan and identify potential junior research positions and funding sources. The Nursing Post-Doctoral Program in Cancer and Health Disparities addresses a critical need related to the nation's nursing workforce, and does so in a way that addresses key barriers that have contributed to the nursing shortage. To our knowledge, there are no post-doctoral programs in Nursing in the US that have been developed and implemented by a college/school of nursing and a clinical partner. The study team includes outstanding clinical and research expertise at both partner institutions (Dr. Greer Glazer, Dean, and Dr. Laura Hayman, Associate Dean for Research, UMB CNHS;, Dr. Pat Reid Ponte, Senior Vice President for Patient Care Services and Chief Nurse at DFCI, and Associate Professor at CNHS, and Dr. Donna Berry, Director of the Phyllis F. Cantor Center for Research in Nursing and Patient Care Services at DFCI.). This project will benefit significantly from support provided by the Training and Survey and Statistical Methods Cores. CRITIQUE 1: Significance: 2 Investigator(s): 2 Innovation: 2 Approach: 3 Environment: 2 Overall Impact: Strengths:

• Promising innovative, well designed, and significant project that builds exceedingly well with prior U-56 efforts and outputs.

• Contributes to a well-trained nursing workforce in cancer health disparities research and adds to the pipeline of nurse scientists.

• Links to and benefits from Training and Survey & Statistical Methods Core • Draws exceedingly well with resources from both institutions. • High mutual benefit among partner institutions. • Institutional support lends itself to sustainability. • If project is successful, there is a high potential to create a national model of education that can

be transferred to a number of sites/settings. Weaknesses:

• Need for some expanded details of the proposed ‘core curriculum content’ on health disparities


• Some added details about evaluation are warranted and how improvements will be infused into the program.

• Integration and linkage to outreach activities could be strengthened. 1. Significance: Strengths:

• Addresses an urgent need to bolster the nursing work force in the preparation of minority and non-minority doctorally prepared nurses who can teach at the university level and conduct independent nursing research.

• Contributes to a diverse cadre of nurse leaders/researchers for impacting cancer health disparities.



• This project is led by key senior leaders, Dr. Patricia Reid-Ponte, Senior VP Nursing and Patient Care Services at DFCI, and Dean Glazer at UMB

• The nursing mentoring team brings excellent nursing and health disparities expertise (Drs. Berry, Cooley, Allen, Hayman, Stuart-Short, Desanto-Madeya and Smith) with funded backgrounds.

• Secondary non-nurse mentors also contribute highly to the interdisciplinary focus of the project • Scholarly outputs of team are excellent and include eight joint publications.



• The aspect of bringing together a college and a clinical partner offers novelty and adds to the clinical and research depth of the program.

• Traditional (year round) and non-traditional tracks (summers) offer an interesting innovation to meet the needs of diverse participants by reducing barriers that have often added to the nursing work shortage.



• Components of the curriculum entail three logical aspects: educational training; research training; and professional development.

• Post-doctoral training program builds exceedingly well on the team’s prior efforts including an accelerated BSN-to-PhD and a post-master’s certificate program (under review). Prior efforts offer an underlying strength and solid infrastructure for contributing to a nationally recognized program. Also, a prior ARRA grant provides infrastructure for the conceptual idea of the first post-doctoral fellowship.

• The program aims to have at least two traditional and three non-traditional students (summer months), which offers novelty and shows flexibility in meeting the needs of non-traditional trainees. Planning efforts take into account some of the traditional barriers to nursing post-docs.

• Recruitment processes are sufficient and targeted. • Integration into DFCI post-doctoral program office bolsters socialization opportunities. • Opportunity to blend cancer health disparities content with existing UMB policy curriculum is

highly consistent with national imperatives relating to health disparities.


• IAC offers ongoing guidance to the project and there is evidence of high integration into the overall partnership

• Nice blend of campus supportive activities for post-doctoral fellows: identification of off-site activities will be important for the non-traditional students.

Weaknesses: • An attractive element of the post-doctoral training is the tailored nature of the program; however,

a draft list of topics that would be covered to show depth and breadth of cancer health disparities topics to be addressed is not provided. How much time is dedicated to the various components? How do the trainee interests fit with the mentors’ existing funded activities to ensure high synergy and productivity?

• Evaluation will be in terms of effectiveness and quality. For example, training experience is evaluated by trainees’ evaluation; mentors evaluation and quantitative evaluation (#papers, grants). However, knowledge/skill or other unique applications of knowledge benchmarks for impacting health disparities are not well delineated.

• Evaluation will be addressed mainly by Methods Core. How is feedback going to be infused in back into the program to enhance improvement?

• Some tracking of socialization activities/networking would seem to be warranted especially among non-traditional students who take part from more distant settings

• Opportunity to link to the outreach program and activities is somewhat underplayed and could offer an added strength to the developing program.


• Exceptionally strong environment(s) that seems well suited to both institutions to receive mutually benefit from the project.

• High institutional support for project from both partners. • Link to other campus resources/cores/people at both sites is exceptional, e.g., Cantor Center,

statistical cores Weaknesses:

• No link to existing and planned community engagement and outreach activities was provided. Additional Review Criteria Protections for Human Subjects: Acceptable

• Note to Program Director: Investigators state that there are no human subjects. Depending on sources of data and potential use of data, there may be need for IRB?

Inclusion of Women, Minorities and Children G1A M1A C3A CRITIQUE 2: Significance: 3 Investigator(s): 1 Innovation: 2 Approach: 3 Environment: 1 1. Significance: Strengths:


• There is a clear need to increase the number of advanced degree nurses at academic health centers in this country to advance nursing research an education.

• The focus of the program on cancer and health disparities will provide an unmet need. Weaknesses:

• For a U54 Training Program the proposed program is fairly narrow, with its singular focus on nursing.


• The faculty members are exceptional, with funded research projects in cancer. Weaknesses:


• Nursing post-doctoral program focused on cancer and health disparities is very unique. • The U56 supported partnership produced a previously non-existent cancer focus. • The effort to develop a non-traditional model to accommodate people with limited ability to

participate in traditional post-docs is innovative. Weaknesses

• No major weaknesses noted. 4. Approach: Strengths:

• The program is structured and comprehensive with didactic, research (independent with mentor) and professional development components.

Weaknesses: • The non-traditional program does not allow sufficient interaction with the mentor. The post-doc is

only on site in Boston for 3.5 months each year. Skype and e-mail contact will at other times. • If the non-traditional program participants are primarily at a separate “home institution”

presumably they will be paid a salary for activities at that home institution, and therefore unable to dedicate sufficient effort to their post-doctoral research project.


• The UMB has an existing graduate training program in nursing, so has the experience and faculty to provide the didactic and professional development component. DFCI provides the cancer research opportunities.


CRITIQUE 3: Significance: 2 Investigator(s):1 Innovation: 2 Approach: 3 Environment: 2 1. Significance: Strengths:

• Designed to ensure a diverse and highly trained work force to fulfill the nation’s nursing faculty needs and to increase the number of nurse researchers with cancer disparities foci.

1 U54 CA156732-01 45 ZCA1 SRLB-3 (O1)EMMONS, K Weaknesses:

• No major weaknesses noted. 2. Investigator(s): Strengths:

• Dr. Glazer (UMB) is dean and professor of nursing. She has extensive experience building new training programs and has published and received funding in the area of underrepresentation of minorities in nursing and cancer health disparities. She will serve as program leader providing strategic direction to internal workgroup responsible for post doctoral fellowship at meetings, and disseminate the program.

• Dr. Hayman (UMB) is associate dean for research and professor of nursing. She has mentored pre-and postdoctoral fellows and faculty in nursing, behavioral and social sciences, and public health. She has received awards for mentorship and teaching. Her role will be co-leader of the mentoring component of the program project. She will lead the post doctoral fellowship program, supervise mentors, and meet with post-docs regularly.

• Dr. Reid-Ponte (DFC/HCC) is the senior vp for patient care services and chief nurse at the DFCI. She is also director of oncology nursing and clinical services at Brigham and Women’s Hospital. She has published in the area of increasing minority representation in nursing. She will serve as the program leader, providing strategic direction, co-lead monthly meetings, and disseminate the program.

• Dr. Berry (DFC/HCC) is the director of the center for research in nursing and patient care services. She has a well-established history of mentoring nurse scholars and scientists.

• Several nursing and non-nursing faculty (mentors) and post-docs (mentees) as well as a program coordinator and web-site specialist will be involved in the program project.



• Investigators point out that there are no post-doctoral programs in Nursing in the U.S. that have been developed and implemented by a college/school of nursing and a clinical partner.



• Both a traditional and non-traditional post-doctoral training model is proposed. • An internal advisory committee will provide oversight and direction for the program. • Program will be constantly evaluated. • Sustainability issues have been addressed.

Weaknesses: • No information is provided to determine how the program will ensure that at least 50% of

mentees are minorities. 5. Environment: Strengths:

• Well-suited within which to conduct the proposed program. Weaknesses:

• No major weaknesses noted.

1 U54 CA156732-01 46 ZCA1 SRLB-3 (O1)EMMONS, K THE FOLLOWING RESUME SECTIONS WERE PREPARED BY THE SCIENTIFIC REVIEW OFFICER TO SUMMARIZE THE OUTCOME OF DISCUSSIONS OF THE REVIEW COMMITTEE ON THE FOLLOWING ISSUES: ADDITIONAL REVIEW CRITERIA: PROTECTION OF HUMAN SUBJECTS (Resume): HS44. Investigators state that there are no human subjects. Depending on sources of data and potential use of data, there may be need for IRB. INCLUSION OF WOMEN PLAN (Resume): G1A INCLUSION OF MINORITIES PLAN (Resume): M1A INCLUSION OF CHILDREN PLAN (Resume): C3A VERTEBRATE ANIMALS (Resume): A10 COMMITTEE BUDGET RECOMMENDATIONS: The budget was recommended as requested. BUDGETARY OVERLAP: None ASSESSMENT: Outstanding PROJECT 5 - Promoting Utilization of Cancer Early Detection Methods among Latinos in Church: (Description as provided by applicant) This community-based participatory research outreach proposal represents a significant shift in focus, from intervention delivery on an individual level, to a focus on enhancing the capacity of community organizations to activate collective resources to translate available evidence to address their priorities and needs. Our aim is to develop an organizational-level intervention to enable communities to adopt, adapt, implement and sustain evidence-based interventions (EBls) to address cancer disparities among Latinos. We target faith-based organizations, since they play a highly prominent role in Latino community life, provide a trusted resource for spiritual guidance, communication, social support, and provide access to a large segment of the Latino population. This three-phase study will: (1) improve understanding of the organizational infrastructure, skills and resources required by Latino churches to implement EBls for cancer control, (2) develop a capacity-building intervention; and (3) test the intervention's effectiveness in a randomized trial with churches as the unit of intervention and analysis, in which churches will be assigned to either a "Capacity Enhancement" (CE) intervention ora "Standard Dissemination" (SD) condition. This study will greatly accelerate the research productivity of Dr. Jennifer Allen, co-PI, Assistant Professor at the Dana-Farber and Harvard Medical school. Co-PI Dr. Maria Idali Torres, Director of the Gaston Institute for Latino Community Development and Public Policy and senior faculty member at UMB, has an established track record of leading large-scale community-based research, and can provide excellent mentorship for Dr. Allen. Dr. Allen's aims to become a leading researcher in the field of dissemination science to eliminate cancer disparities. Both the Survey and Statistical Methods Core and Training Core will significantly contribute to this project. CRITIQUE 1: Significance: 2 Investigator(s): 1 Innovation: 1 Approach: 3 Environment: 1

1 U54 CA156732-01 47 ZCA1 SRLB-3 (O1)EMMONS, K 1. Significance: Strengths:

• The primary aim of the study is to develop an organizational-level intervention to enable Latino faith-based organizations, Catholic ones with >60% Latinos, to adopt, implement and sustain evidence-based interventions to address cancer disparities among Latinos.

• The study will be conducted in three phases over a three year period: (1) examine the organizational factors required by Latino churches conducting EBIs for cancer screening; (2) develop a capacity-building intervention; and (3) test the capacity-building intervention in an RCT comparing a ‘capacity enhancement’ intervention with a ‘standard dissemination’ intervention.

• The significance of the study is that there is an urgent need to disseminate evidence-based interventions through existing community structures and channels. There is a particularly critical need to address Latinos cancer risk and mortality. Because most churches, particularly Latino churches, lack the organizational capacity, skills and resources to implement health promotion activities, it is critical to explore the characteristics of religious organizations that are associated with sponsoring health promotion programs. While faith-based health interventions have been studied extensively in African American communities, few studies have examined the implementation of EBIs in Latino churches.

• If successful, the proposed study will provide critical and useful information on the organizational characteristics associated with implementing cancer control EBIs, particularly among Latino Catholic churches.

Weaknesses: • Not clear if the EBIs that are being considered for implementation are for cancer screening

specifically or cancer control more generally.


• The Co-PIs, Drs. Allen and Torres, and research team seem extremely well positioned to conduct the proposed study. Dr. Allen is a scientist in the Center for Community-Based Research and the Cantor Center for Nursing Research at DFCI and an Adjunct Asst Prof in the Harvard SPH. She has extensive experience in CBPR approaches to cancer control interventions, particularly among women of color.

• Dr. Torres is an Associate Prof of anthropology and the director of the Mauricio Gaston Institute for Latino Community Development and Public Policy at UMass-Boston. Her PhD and professional expertise are in applied medical anthropology, particularly ethnographic research in Latino communities. These leaders, along with the other team members, represent an impressive and comprehensive team to guide the proposed study.



• This project shifts the focus of dissemination from the characteristics of innovation to the organizational context in which programs would be expected to be conducted and sustained.

• Other innovations include: the focus on develop an organizational-level/ capacity building interventions; Latino faith-based organizations; and the organizational context in which EBIs are conducted.

Weaknesses: • There are no notable weaknesses. The only minor point is that the figure indicates that there are

three Specific Aims for the study but the Specific Aims section only indicates two Aims.



• The three phases of the study seem to build logically on one another and each will provide useful information for the project.

• The use of measures for the Phase 1 study and Phase 3 RCT seem well thought out and comprehensive.

• The Phase 2 plan for how to adapt the program for the setting also seems congruent with the literature and well designed.

• The analysis plan also seems well developed and adequate. Weaknesses:

• There is no mention of the number of key informant interviews. • It is not clear if simultaneously focusing on adapting EBIs that address breast, cervical and

colorectal screening will be too difficult and time consuming. The adaptation process outlined is quite comprehensive and may be time consuming. It is not clear if there may be more than one EBI adapted per cancer, which would mean that there could be as many as 5-6 interventions that need to be adapted during this time.


• The investigative team, Scientific Advisory Committee, and Community Advisory Committee are outstanding.

• How the team plans to utilize the center resources to support and enhance this intervention also is impressive and maximizes the resources of the proposed center.

• The universities and institutional support are certainly adequate and build on the collaborative relationships of both investigators.


CRITIQUE 2: Significance: 2 Investigator(s): 3 Innovation: 3 Approach: 2 Environment: 4 1. Significance: Strengths:

• Need for interventions to promote dissemination of existing evidence based interventions for cancer prevention, particularly among health disparite populations, and link to potential reduction in cancer mortality

• Potential for addressing lower cancer survival rates among Latinos arising from diminished access to early detection and treatment services

• Potential for increased community capacity in organizations serving Latino population (churches) to impact health outcomes



• Project PIs have extensive community based research and clinical experience. • PIs bring strong research track record with complementary research expertise to project • PIs have been involved in multiple community research collaborations • PI expertise is appropriate for a community outreach research project


• Other staff bring expertise in community intervention in the target population, qualitative data collection, instrument design, health education

• Project guidance and oversight is provided by a community advisory board (existing, to be enhanced) and an established scientific advisory committee

• Two working groups will meet biweekly to develop evaluation and intervention protocols Weaknesses:


• The emphasis on building capacity within Latino church organizations for cancer prevention is innovative

• The conceptual framework integrates theories of organizational change, diffusion of innovations, and community capacity building



• The approach builds on lessons learned from previous research in Latino churches • The research design includes three phases that includes the following strengths: 1) formative

research to understand characteristics important for intervention adaptation; 2) a baseline survey of church organizational characteristics upon which will aid in cultural and organizational adaptation of evidence based cancer prevention interventions to the targeted settings; 3) a randomized trial with sufficient power to answer the hypotheses

• PIs have considered of the strengths and limitations of the selected approach and alternative strategies

• This project would bring a substantive research emphasis to the outreach program. • U54 objectives include Outreach Objectives, which are congruent with this project

Weaknesses: • Providing a menu of activities to each church implies that there may be a large degree of

variability in the intervention delivery components and dose. Process evaluation procedures are in place that will hopefully capture these variations

• 5. Environment: Strengths:

• Previously completed work suggests that both community and institutional resources are in place to accomplish this project

• The project builds upon the resources and expertise of the training core and survey and statistical methods core

Weaknesses: • The outreach aspect of the overall U54 seems to still be at a very developmental point. This

project should further and strengthen this effort, but may be hampered by the lack of a strong outreach focus of the overall program and partnership

Additional Review Criteria Protections for Human Subjects:

• Acceptable – risks are minimal Inclusion of Women, Minorities and Children G1A M1A

1 U54 CA156732-01 50 ZCA1 SRLB-3 (O1)EMMONS, K C3A

• Primarily minority – Hispanic/Latino • Data are collected from church organizational representatives, who are all adults

CRITIQUE 3: Significance: 3 Investigator(s): 2 Innovation: 4 Approach: 3 Environment: 2 1. Significance: Strengths: There is an urgent need for dissemination of evidence-base interventions (EBI) to minority populations. Implementation of available cancer prevention and screening strategies will greatly reduce the cancer mortality rate in the US. Targeted efforts as proposed in this project to a target group (Latinos) will decrease the gap in some areas of cancer disparities. Using churches as a mean of delivering community-based participatory research focus on capacity building of community organizations to address and prioritize their needs. Latinos experience a disproportionate burden of cancer mortality. Interventions to promote church capacity to implement EBIs are needed. Identification of the targeted churches in the previous planning grant will greatly enhance the feasibility of this project. Weaknesses:

• No major weaknesses noted. 2. Investigators Strengths: Dr. Jennifer Allen is the co-PI and is an Assistant Professor at the Dana-Farber and Harvard Medical School. Dr. Torres is the Director of the Gaston Institute for Latino Community Development and Public Policy. She is also a senior faculty at UMB. Weaknesses No major weaknesses noted. 3. Innovation Strengths: The use of churches for this particular ethnic group is innovative. The use of churches to address priorities and needs affecting a population will greatly enhance its importance and increase its intervention goals of lowering cancer reduction and mortality rates. Weaknesses The use of community-based participatory research is not innovative 4. Approach Strengths: The approach is appropriate to conduct this type of research. The study team used the U56 to focus on cancer screening in Latino churches, and this allowed them the opportunity to conduct the framework for the present study. Weaknesses No major weaknesses noted.

1 U54 CA156732-01 51 ZCA1 SRLB-3 (O1)EMMONS, K 5. Environment Strengths: The environment is suitable for this proposed research project. Weaknesses No major weaknesses noted. THE FOLLOWING RESUME SECTIONS WERE PREPARED BY THE SCIENTIFIC REVIEW OFFICER TO SUMMARIZE THE OUTCOME OF DISCUSSIONS OF THE REVIEW COMMITTEE ON THE FOLLOWING ISSUES: ADDITIONAL REVIEW CRITERIA: PROTECTION OF HUMAN SUBJECTS (Resume): HS30 INCLUSION OF WOMEN PLAN (Resume): G1A INCLUSION OF MINORITIES PLAN (Resume): M1A INCLUSION OF CHILDREN PLAN (Resume): C3A VERTEBRATE ANIMALS (Resume): A10 COMMITTEE BUDGET RECOMMENDATIONS: The budget was recommended as requested. BUDGETARY OVERLAP: None ASSESSMENT: Excellent 09 CORE 1 - Career Development Plan (Description as provided by applicant) Shared resources are an integral part of this U54. Across the two applications, two cores are presented the Survey and Statistical Methods (SSM) Core, and the Training Core. The cores are shared across both institutions, and will improve the research capacity in the partnership. The SSM Core will leverage resources from UMB and DF/HCC to improve study design and evaluation methods, to build investigators' skills in these areas, and to support future research from the partnership. The Training Core will integrate, standardize, and strengthen training activities across all parts of the partnership, and will oversee the evaluation of student training outcomes. Due to space limitations of the application, although both cores will provide services to investigators at both institutions and are jointly co-led by DF/HCC and UMB faculty/staff, only the SSM Core description is provided in this application. The Training Core is described in the UMB application. CRITIQUE 1: Strengths:

• Strong rationale given for having a primary mentor. • Provision of salary support will likely lead to strong interest on part of mentors to pursue role

seriously. • Training in Conduct of Research included throughout. • Good descriptions of institutional support for some career development plans. • Good recognition of the importance of career development.

Weaknesses:


• Career Development Core does not mention the following: o What to do in cases of conflict between mentor and mentee o How to evaluate success of mentoring plan progress o For some, how goals will be attained; specificity of goal-attainment not included in many

plans o Some plans have little discussion of primary mentors

• Career development plans are uneven; do not always describe candidate; how candidate interacts with mentor(s), etc.

• Collaboration on grant writing not discussed. • Collaboration on the included proposals not always discussed. • Some junior faculty do not discuss products as a result of their mentorship. • ER Park: strong publications; strong research; how she will attain career development goals not

specified other than to work with mentors; meeting frequency not described; is primary mentor for L. Traeger which may be somewhat premature.

• L. Traeger: Excellent description of how goals will be met; describes how often faculty will meet with mentors; no biosketch included; no institutional support section.

• R. Jimenez: Not clear how often she will meet with mentors; not clear how her goals will be attained; some concern about her time availability during residency; no biosketch given; no institutional support section.

• N. Gray: Excellent collection of mentors; little description of mentors; excellent publication record; strong research experience; no institutional support section.

• P. Yang: Focuses mainly on TBN post doc fellow; does not describe goals or how they will be attained; does not discuss mentors, no instiutional support section.

• Nurse Post-doc trainees: proposes plan for developing career development plans once trainees are identified; assigns primary senior and junior mentors.

• J Allen: no description of Dr. Allen’s background and how she will work on the project. Plan emphasizes establishing mentoring structures once grant is funded, little discussion of career development goals and how they will be attained

CRITIQUE 2 Strengths:

• Well experienced. Weaknesses:

• Not defined how they will address goals • It is not clear that the mentoring plan is adequate and targeted to needs. • Needs are not clearly defined.

COMMITTEE BUDGET RECOMMENDATIONS: The budget was recommended as requested. BUDGETARY OVERLAP: None ASSESSMENT: Satisfactory 10 CORE 2 - Resource/Infrastructure Development Core (Description as provided by applicant) The Planning and Evaluation (P&E) Core is responsible for establishing the Partnership's goals and objectives (see 3.A.), devising strategies to accomplish those goals, and for evaluating and monitoring the overall progress and impact of the Partnership. This section details the planning and evaluation activities of the Partnership and provides justification for the resources requested to carry out these functions. The U56 funding allowed the Partnership to engage the faculty broadly, to establish organizational structure, and to support and evaluate pilot projects and programs in research, training, and outreach (see S.A). These functions will continue within the U54 P&E Core.

1 U54 CA156732-01 53 ZCA1 SRLB-3 (O1)EMMONS, K CRITIQUE 1: Strengths:

• Survey and Statistical Methods (SSM) Core and Developmental Core are presented under Dr. Emmons and Dr. Colon-Carmona applications separately. SSM Core is based at DFCI while Survey Research segment of SSM and the Training Core is based at UMass Boston.

• Clear goals for these cores are stated: methodological consultation, seminar series for training, and to create an incubator for research ideas, pilots, methods are presented.

• Outstanding leadership (Co-Directors (Dr. Colon-Carmona and Emmons). • SSM core is well led and well staffed. Investigators have strong publication records and grant

writing skill. • Survey Research (SR) at UMB has strong personnel and capacity. • SR has physical infrastructure needed to conduct survey research reliably and effective. • SR has survey sampling methodologic capacity. • SR also has substantial Computer Assisted Telephone Interviewing (CATI) capacity. • Training core targets appropriate research skills needs for graduate students and junior faculty in

effort to serve research incubation role. • Long term effective collaboration between sites which are geographically close yet quite diverse. • Strong scientific mentoring for junior faculty and trainees built into DFCI, while UMB shares

commitment to introducing urm students into research and clinical environments. (40% of undergraduate populations at UMass-Boston are underrepresented minority students).

• The investigators demonstrate good conceptualization of what collaboration needs of each site are and how those needs can be met in mutually beneficial way.

• Demonstration of understanding of communication needs for collaboration demonstrated in “Lessons learned” document. Thus, social infrastructure of Training and Development Cores appear to be intact as well.

• Proven track record of gaining research grants from the collaboration ($29 million) and training grants ($13 Million) demonstrates that SSM and Training Cores are serving their functions well.

• Potential to train urm doctoral researchers in 8 fields at UMB. • Presence of meaningful contribution of resources from each institution demonstrates reciprocal

nature of collaboration. • The investigators indicate 83 collaborative publications: 35 joint authorships; 31 direct result of

partnership; 17 publications by junior faculty trainees demonstrate both productivity of SSM core as well as Training core.

• Development of seed funds from U56 (both pilot and pre-pilot level; 19 awarded to date), DHCC pilot funding (2 pilots per year: $150,000 over two years for each), external sources for research funding ($26 million to date; $13 million in training funds to date).

• Success in using each source to establish ongoing research; the preliminary data are presented from these other mechanisms.

• Participation of UMB collaborators in important UMB new faculty hires. • Organization structure is clear; roles of committees clear and there is a track record of good

function. • Administrative core composed of UMB component and DFHCC component which will

communicate on at least a bi-weekly basis. • Clear delineation of problem solving processes and responsibilities and communication

mechanisms. • Clear mechanism for soliticiting proposals and evaluating proposals. • Strong external review panel who have been given clear criteria for evaluating

Weaknesses: • Minimal description of how the SSM core is being applied to process measurement of overall

goals of project. CRITIQUE 2:

1 U54 CA156732-01 54 ZCA1 SRLB-3 (O1)EMMONS, K Strengths: Across the two applications, two Cores are presented—the Survey and Statistical Methods (SSM) Core, and the Training Core. The cores are shared across both institutions, and will improve the research capacity in the partnership. The SSM Core will leverage resources from UMB and DF/HCC to improve study design and evaluation methods, to build investigators' skills in these areas, and to support future research from the partnership. The Training Core will integrate, standardize, and strengthen training activities across all parts of the partnership, and will oversee the evaluation of student training outcomes The SSM Core description is provided in this application. The Training Core is described in the UMB application. There is a description of the Coordination of Responsibilities and how they will be accessing, tracking and evaluating Services. There is a description of the services to be provided. The SSM Core will offer three types of services, support for funded projects, training in the design and conduct of survey research and a research incubator (foster new collaborations). The UMB partner will contribute the expertise and resources of the UMB Center for Survey Research (SR) which is located on the UMB campus and has excellent proximity to the faculty and students who will be involved in U54 activities, as well as to faculty who could potentially become involved in the future. SR is a full scale academic survey research center with professional telephone and in-person interviewing staffs, computer assisted telephone facilities, and survey sampling capacity. sSR conducts basic and applied research, and provides consultation and technical support to public and private agencies and university scholars. Senior staff members include nationally recognized scholars in survey methodology, health services research, and substance abuse research. Their experience includes substantial biostatistical expertise, including authorship of a wide range of published analyses in medical and public health journals. SR has a Computer Assisted Telephone Interviewing (CATI) system on 35 stations; the capacity for in-person Computer Assisted Personal Interviewing (CAPl), Internet data collection; and a specialized coding department. CSR has significant experience designing survey instruments and interviewing in a range of foreign languages, www.csr.umb.edu. The DF/HCC partner will draw on the expertise and resources of the Data Technologies Core (DTC), housed within the Center for Population Sciences at DFCI. The DTC is dedicated to the implementation of rigorous quantitative and qualitative survey research in community and clinical settings. The Data Core provides expertise and technical support for developing and implementing data collection protocols, quality control of data collection processes, and data management. Its capabilities include the development and implementation of survey research projects, including Internet, mail, and face-to-face interviewing, project evaluation, cognitive interviewing, focus groups, in-depth interviews, and qualitative data analysis. The Core's experienced staff, which represents a range of behavioral research and survey methods expertise, supports basic and applied cancer-related research projects involving community, patient, and family samples. Through their collaboration, SR and DTC bring considerable synergy to the Partnership. The proposed resources in these Cores are well-described and will contribute significantly to a successful completion of the project. The experience, leadership, organizational abilities, and expertise of the leadership staff is documented and is adequate to conduct the Core. The expertise of the staff at each partner is adequate to conduct the project. Weaknesses: The contributions of the proposed resources/infrastructure to the overall priorities are not properly delineated. It is not clear whether the qualifications of key personnel to operate the Core are adequate.

1 U54 CA156732-01 55 ZCA1 SRLB-3 (O1)EMMONS, K COMMITTEE BUDGET RECOMMENDATIONS: The budget was recommended as requested. BUDGETARY OVERLAP: None ASSESSMENT: Exceptional 11 CORE 3 - Planning and Evaluation Core (Description as provided by applicant) The Planning and Evaluation (P&E) Core is responsible for establishing the Partnership's goals and objectives (see 3.A.), devising strategies to accomplish those goals, and for evaluating and monitoring the overall progress and impact of the Partnership. This section details the planning and evaluation activities of the Partnership and provides justification for the resources requested to carry out these functions. The U56 funding allowed the Partnership to engage the faculty broadly, to establish organizational structure, and to support and evaluate pilot projects and programs in research, training, and outreach (see S.A). These functions will continue within the U54 P&E Core. CRITIQUE 1: Strengths:

• IAC has excellent members who are well-qualified to do this work. • Strong PSC with Chair who establishes continuity throughout the life of the partnership from U56

to this application. • Plans to recruit new faculty in both institutions. • DF/HCC commitment of resources for training is a strength. • Teaching fellows have opportunity to teach at UMB. • Efforts to increase research component of the outreach core. • Subcommittees of the IAC are a good idea. • Good plan for determining premature outcome of each project. • Good discussion of how ongoing projects will be monitored. • Evaluation of the training core is strong.

Weaknesses: • Generally missing from this Core is a discussion of how new proposals are identified and

reviewed to make sure the overall “package” meets the goals of the partnership; an earlier section speaks of an external review for the U56, but this is not emphasized in this iteration.

• Details on the symposium and workshops are lacking; not clear how those events will expand collaborations.

• No details on how potential new collaborators will be identified and encouraged to participate are provided.

• Outreach Core is somewhat limited with much service and only one project proposed that addresses outreach research. Would encourage more outreach projects

• Not clear how the subcommittees deal with conflict between the subcommittees when competing projects are proposed.

• Role of CHE in Outreach Core unclear.

CRITIQUE 2: Strengths:

• Planning structures/committees are in place to undertake various aspects of planning, including 1) an established Executive Committee that meets monthly, 2) an Internal Advisory Committee with 3 distinct focus-related subcommittees which foster collaboration and research expansion, provide internal review and evaluation of developmental and pilot projects, and 3) a Program Steering Committee that provides external annual evaluation


• Planning activities are identified related to fostering collaborative research, develop the training program, and developing outreach, basic science, population science, and training

• The Internal Advisory Committee includes three subcommittees covering the three primary focus areas of the research. Chairs/co-chairs are well-qualified for their roles.

• Program Steering Committee chair has served since inception of U56. Program Steering Committee membership includes expertise that encompasses the major focus areas for research of the proposed U54 as well as geographic and ethnic diversity.

Weaknesses: • Qualifications of the IAC training subcommittee members for their roles are not described. • Plans to develop the outreach area seem to lack any specific plan for incorporating research into

outreach. • The internal evaluation processes described include evaluation activities and measures but lack

detail regarding implementation procedures and measures. • The description of the Program Steering Committee functioning is not described in sufficient

detail to evaluate whether the plan for using it is effective. COMMITTEE BUDGET RECOMMENDATIONS: The budget was recommended as requested. BUDGETARY OVERLAP: None ASSESSMENT: Satisfactory CORE 4 - Administrative Core (Description as provided by applicant) The Administrative Core is comprised of two components, one based at DF/HCC and the other at UMB. At DF/HCC, the Administrative Core includes both scientific and administrative leadership. Scientific oversight is provided by Dr. Emmons, along with Dr. Holly Prigerson, (Associate Professor, DFCI; Associate Director of DF/HCC's lECD), and Dr. Sarah Weiler (Associate Director for Operations and Program Coordination, DF/HCC). Administrative oversight is provided by Ms. Karen Burns White (Associate Deputy Director of the lECD), Ms. Nancy Klockson (Dr. Emmons' Administrative Assistant), and Ms. Gail Dudley (DFCI Departmental Grant Management Specialist at DFCI, who supports Dr. Emmons' research portfolio). Ms. Burns White, serves co-Director of the Training core. She oversees student training and community outreach for the DF/HCC, among other leadership roles within the lECD. She will work closely with the U54 Community Health Educator (CHE), and together they will ensure that there is a robust portfolio of community outreach activities. The U54 Administrative team will work with the DF/HCC Community Engagement Committee and its community partners to conduct a needs assessment related to outreach, and to develop a plan for outreach activities. It is anticipated that there will be one health fair held per year, as has happened throughout the U56 funding period, as well as a wide range of outreach service activities. Future U54 outreach activities will be decided in collaborations with community partners, however, exemplars based on past efforts include a speaker series on cancer and cancer prevention during National Minority Cancer Awareness Week, a cancer education display at neighborhood library branches, informational sessions on cancer clinical trials at local community health centers, and training and support of peer leaders in local subsidized housing communities. The CHE will be an integral member in linking with the activities of the Massachusetts Cancer Control Plan. Ms. Burns White, together with the CHE, will design and implement outreach service activities, with a comprehensive needs assessment in Year 1, and where possible engage faculty and provide opportunities for trainees to participate. CRITIQUE 1: Strengths: Administrative Core is headed by Dr. Emmons at DFCI and Dr. Colon-Carmona at UMB. Dr. Emmons has served as the DF/HCC PI since the Partnership's inception. Dr. Colon-Carmona became UMB PI in

1 U54 CA156732-01 57 ZCA1 SRLB-3 (O1)EMMONS, K year 2 of the current funding period, and has formed an excellent partnership with Dr. Emmons. The PIs have complementary backgrounds and expertise, which will assist to facilitate development of a broad-based collaboration that crosses disciplinary boundaries. Dr. Emmons is a highly experienced, independent investigator who holds significant leadership positions within DF/HCC and Harvard School of Public Health. She has a strong track record of mentorship, as noted by her receipt of several institutional and national mentoring awards (e.g. Harvard Medical School's Harold Amos Diversity Award, Society of Behavioral Medicine's Research Mentor Award). As a senior scientist at DFCI and Professor and Associate Dean of Research at Harvard School of Public Health, she is well positioned to bring key people together, and has the ability to impact policy. Facilitated by her efforts, the team has created a climate of reciprocal institutional commitment in which the Partnership is viewed as a high priority. As the Partnership moves to the level of full comprehensive status, the leadership team will be expanded in order to maximize stability. Dr. Holly Prigerson, an Associate Professor at Dana-Farber Cancer Institute and Harvard Medical School, will work with Dr. Emmons to provide leadership for the U54 at DF/HCC. The Administrative Core provides five primary functions: 1) leadership, 2) administrative support, 3) assurance of implementation of Partnership goals and objectives, 4) coordination of communication among all Partnership members, including the IAC and PSC, and 5) oversight, financial stewardship of funds, and implementation of the evaluation of the Partnership. It will coordinate all aspects of the Partnership, provide administrative and logistic support for Partnership activities including regular meetings and transportation between the Partners, and ensure that all Partnership activities are tracked, implemented on the proposed timeline, and use methods as proposed. All procedures and processes were developed in the early stages of the U56, and thus are well established. The administrative leadership team is quite stable, has a long track record of collaboration, and thus highly functional. The Administrative Core is comprised of two components, one based at DF/HCC and the other at UM. The two Administrative components have a demonstrated track record of effective collaboration. For example, Drs. Grosovsky and Hayman in collaboration with Dr. Sarah Weiler of the DF/HCC have been instrumental in the development of collaborations. Dr. Joan Becker is principal investigator and Director of several training programs at UMB, which she and Ms. Burns White have effectively leveraged to maximize training opportunities in the context of the U56, and to increase our competitiveness for new training grants. Weaknesses:

• Sufficient evidence of administrative integration of the proposed partnership is not provided. • It is not clear whether the proposed quality of organizational and administrative structures

adequate for the effective attainment of the priorities and objectives of the Partnership. • The investigators have not demonstrated whether the use of the administrative core services by

the budgeted activities and projects/programs is appropriate. CRITIQUE 2: Strengths:

• Outstanding leadership (Co-Directors (Dr. Colon-Carmona and Emmons) that has demonstrated a solid U56 partnership exemplified by productive outputs, solid communications and increasing collaborations. Dr. Carmona is Associate Professor of Biology (UMB) and studies the cytoskeleton and cell signaling pathways associated with growth control, and brings an extensive background in education and training of diverse student populations. Dr. Emmons is a senior behavioral scientist at DFCI with a strong track record of funded research in theory-based approaches to cancer prevention in underserved populations. Both PIs are well qualified to co-lead the core and complement each others’ strengths quite well.


• Administrative Core builds exceedingly well on the strengths and infrastructure that resulted from prior U-56 efforts, and thus, enhance the likelihood of attainment of partnership priorities and objectives.

• Mutual benefit among collaborating partners is evident and a keen strength. • Proposed Administrative Core structure, operational processes, responsibilities and

communications are delineated and integrated into the partnership to a high degree. The Core offers standard support functions across various components of the Partnership, as well as specialized support.

• Administrative Core has appropriate outline, description and detail of administrative functions including leadership, executive committee, PSC, IAC, fiscal aspects and community activities, identifying career development opportunities and assistance with IRB/regulatory activities and recruitment activities, e.g., UMB devoting an endowed Chair, the Alton Brann Distinguished Professorship, to Partnership-related activities

• Lessons learned from U-56 provide a blueprint of ‘next step’ activities which are included and show attention to ongoing improvement measures.

• Outstanding track record of team’s ability to leverage funding which poises the Core to continue advancing this important role.

• Strong credentials and diversity of PSC and IAC membership are in place • Well-established communications processes and mechanisms that appear to have been highly

effective and sets the stage for next steps. Weaknesses:

• Details of how the CHE (key integral role) interacts with the Administrative Core are lacking. CHE as outlined in RFA should be member of IAC and demonstrate linkages to NCI. Also, would have liked to see a community member as part of the PSC or other administrative committee to further demonstrate growing outreach focus and reinforce this important aspect of the project for impacting health disparities.

• Communication processes seem well established: yet some added description of how challenges or conflicts are managed and addressed is not provided.

• Description of the evaluation strategies and processes used to monitor partnership are minimally described, though it appears to be the role of the IAC.

COMMITTEE BUDGET RECOMMENDATIONS: The budget was recommended as requested. BUDGETARY OVERLAP: None ASSESSMENT: Exceptional

1 U54 CA156732-01 59 ZCA1 SRLB-3 (O1)EMMONS, K COMMITTEE BUDGET RECOMMENDATIONS The table below summarizes the estimated effects on the original amounts requested by the applicant of implementing the budgetary changes recommended by the reviewers and summarized in the Budget section(s) of the Summary Statement above. The table below does not take into account additional information that may be provided by applicants in response to administrative requests for updates, or additional administrative changes required to meet Institute funding policies, either or both of which may result in a significantly different final recommended budget figure. Consequently, applicants should make no inferences from these figures about what the final budget might be, should an award be possible. The details of the recommended reductions are articulated under the Committee Budget Recommendations for each component.

First Year Requested Direct Costs

First Year Recommended Direct Costs

Administrative Core $112,923 $112,923 Planning & Evaluation Core

$79,489 $79,489

Pilots and Full Projects $284,561 $284,561 Shared Resources Core

$108,624 $108,624

Total Direct Cost

$1,678,546 $1,678,546

NOTICE: In 2008 NIH modified its policy regarding the receipt of resubmission (formerly termed amended) applications. Detailed information can be found by accessing the following URL address: http://grants.nih.gov/grants/policy/amendedapps.htm

MEETING ROSTER

National Cancer Institute Special Emphasis Panel NATIONAL CANCER INSTITUTE

Comprehensive Minority Institution Cancer Center Partnership ZCA1 SRLB-3 (O1) B

June 29, 2010 - June 30, 2010

CHAIRPERSON ISALES, CARLOS MIGUEL, MD PROFESSOR CHIEF PROGRAM IN REGENERATIVE MEDICINE INSTITUTE FOR MOLECULAR MEDICINE AND GENETICS MEDICAL COLLEGE OF GEORGIA AUGUSTA, GA 309123175 MEMBERS ANTONIA, SCOTT J, MD, PHD SENIOR MEMBER DIRECTOR, IMMUNOLOGY PROGRAM H. LEE MOFFITT CANCER CENTER & RESEARCH CTR TAMPA, FL 33612 BETANCOURT, HECTOR M, PHD PROFESSOR DEPARTMENT OF PSYCHOLOGY LOMA LINDA UNIVERSITY LOMA LINDA, CA 92350 CABRAL, GUY A., PHD PROFESSOR DEPARTMENT OF MICROBIOLOGY AND IMMUNOLOGY SCHOOL OF MEDICINE VIRGINIA COMMONWEALTH UNIVERSITY RICHMOND, VA 232980678 CALLAHAN, EDWARD J, PHD PROFESSOR DEPARTMENT OF FAMILY AND COMMUNITY MED UNIVERSITY OF CALIFORNIA, DAVIS SCHOOL OF MEDICINE SACRAMENTO, CA 05817 CASIANO, CARLOS A, PHD ASSOCIATE PROFESSOR CENTER FOR HEALTH DISPARITIES/MOLECULAR MEDICINE CHDMM EDUCATION AND TRAINING CORE LOMA LINDA UNIVERSITY SCHOOL OF MEDICINE LOMA LINDA, CA 92350 ELGAVISH, GABRIEL A, PHD PROFESSOR DEPARTMENT OF BIOCHEMISTRY UNIVERSITY OF ALABAMA AT BIRMINGHAM BIRMINGHAM, AL 35294 FERNANDER, ANITA FAY, PHD ASSISTANT PROFESSOR DEPARTMENT OF BEHAVIORAL SCIENCE UNIVERSITY OF KENTUCKY LEXINGTON, KY 405360086

FIGUEIREDO, JANE C, PHD ASSISTANT PROFESSOR KECK SCHOOL OF MEDICINE UNIVERSITY OF SOUTHERN CALIFORNIA LOS ANGELES, CA 90033 GRIFFITH, DEREK M, PHD ASSISTANT PROFESSOR HEALTH BEHAVIOR & HEALTH EDUCATION CTR FOR RESEARCH ON ETHNICITY, CULTURE AND HEALTH UNIVERSITY OF MICHIGAN SCHOOL OF PUBLIC HEALTH ANN ARBOR, MI 48109-202 JAMES, AIMEE S, PHD RESEARCH ASSISTANT PROFESSOR DEPARTMENT OF SURGERY SCHOOL OF MEDICINE SITEMAN CANCER CENTER WASHINGTON UNIVERSITY IN SAINT LOUIS SAINT LOUIS, MO 63110 LYN-COOK, BEVERLY ANN, PHD SENIOR RESEARCH SCIENTIST DIVISION OF MOLECULAR EPIDEMIOLOGY NATIONAL CENTER FOR TOXICOLOGICAL RESEARCH FDA JEFFERSON, AR 72079 MATSUYAMA, ROBIN K, PHD ASSISTANT PROFESSOR DEPT OF SOCIAL & BEHAVIORAL HEALTH VIRGINIA COMMONWEALTH UNIVERSITY RICHMOND, VA 23298 MEADE, CATHY D, PHD PROFESSOR AND DIRECTOR DEPARTMENT OF INTERDISCIPLINARY ONCOLOGY H. LEE MOFFITT CANCER CENTER AND RES. INST. TAMPA, FL 33612 MILLER, ALEXANDRA CECILE, PHD ASSISTANT PROFESSOR ARMED FORCES RADIOBIOLOGY RESEARCH INSTITUTE UNIFORMED SERVICES UNIVERSITY BETHESDA, MD 20889 MITCHELL, EDITH P., MD CLINICAL PROFESSOR DIVISION OF NEOPLASTIC DISEASES DEPARTMENT OF MEDICINE THOMAS JEFFERSON UNIVERSITY PHILADELPHIA, PA 19107

RAGIN, CAMILLE C, PHD ASSOCIATE PROFESSOR DEPT OF EPIDEMIOLOGY AND BIOSTATISTICS SUNY DOWNSTATE SCHOOL OF PUBLIC HEALTH SUNY DOWNSTATE MEDICAL CENTER BROOKLYN, NY 11203 THOMPSON, BETI , PHD ASSOCIATE PROGRAM HEAD CANCER PREVENTION PROGRAM FRED HUTCHINSON CANCER RESEARCH CENTER SEATTLE, WA 98109 WILLIAMSON, PATRICK , PHD PROFESSOR DEPTARTMENT OF BIOLOGY AMHERST COLLEGE AMHERST, MA 01002 YADRICK, KATHLEEN , PHD PROFESSOR DEPARTMENT OF NUTRITION AND FOOD SYSTEMS UNIVERSITY OF SOUTHERN MISSISSIPPI HATTIESBURG, MS 39406 SCIENTIFIC REVIEW ADMINISTRATOR PALEKAR, LALITA D., PHD SCIENTIFIC REVIEW OFFICER SPECIAL REVIEW AND LOGISTICS BRANCH DIVISION OF EXTRAMURAL ACTIVITIES NATIONAL CANCER INSTITUTE NATIONAL INSTITUTES OF HEALTH BETHESDA, MD 208927405 GRANTS TECHNICAL ASSISTANT SHEPARD, LIANN EXTRAMURAL SUPPORT ASSISTANT SPECIAL REVIEW & LOGISTICS BRANCH DIVISION OF EXTRAMURAL ACTIVITIES NATIONAL CANCER INSTITUTE NATIONAL INSITUTES OF HEALTH BETHESDA, MD 208928329 Consultants are required to absent themselves from the room during the review of any application if their presence would constitute or appear to constitute a conflict of interest.

Documents

U54 Grant Summary Statements