NIBR Postdoctoral Program
Stanford University 21 September 2010
W. Ross Tracey, PhD
Associate Director, Education Office
A B Jefferson, PhD
Investigator III, Cancer Biology, Oncology
Agenda
Novartis and NIBR background
Emeryville: research and postdocs in Cancer Biology
Postdoctoral training program highlights
Novartis at a Glance
Unique portfolio to meet changing healthcare needs:• Leading innovative pharmaceuticals
• High-quality, low-cost generics
• Preventive vaccines
• Consumer health products
World’s third largest pharmaceutical company by sales ($44.3 billion)
One of 20 largest companies by market capitalization
Ranked among most respected companies worldwide
R & D investment of ~ $7.4 billion/year
Our mission at Novartis
We want to discover, develop and market successfully, innovative products to prevent and cure diseases, to ease suffering, and to enhance quality of life.
We also want to provide a shareholder return that
reflects outstanding performance and to adequately
reward those who invest ideas and work in
our company.
Coartem® (malaria):84 million treatments shipped in 2009 – cumulatively delivered 300 million treatments which helped save
an estimated 750,000 lives
Leprosy medication free of charge:>4.5 million patients cured since 2000
TB donations (DOTS):500,000 patients in five years
Global patient assistance:Medicines free or at reduced cost to 143,000 patients, valued
at $1.1 billion
NITD1 in Singapore:Focus on TB, dengue fever and malaria
NVGH² in Siena, Italy:Vaccines Research Institute for neglected diseases
Access to medicine programs –in 2009 we contributed 3.4% of net sales
1 Novartis Institute for Tropical Diseases; 2 Novartis Vaccines Institute for Global Health; 3 Based on approximate market value
2009:
79.5 million patients supported
Programs and research valued at USD $1.51 billion3
Novartis Institutes for BioMedical Research (NIBR)
15 sites worldwide
Approx. 7000 employees globally
Approx. $1.8 billion budget ($1 billion pre-clinical)
Specific centers focus on different disease areas and several platforms
NIBR Sites
Emeryville Cambridge
East Hanover
HorshamRueil/
Malmaison
Basel
Vienna
Madhapur/
Hyderabad
Shanghai
Beijing
Tokyo
NIBR Sites
Translational Sciences Sites
NIBR Disease Areas
Autoimmunity, Transplantation & Inflammation
(ATI)
Cardiovascular & Metabolism
(CVM)
Gastrointestinal (GI)
Infectious Diseases (ID)
Musculoskeletal Disease (MSD)
Neuroscience (NS)
Oncology (ONC) Ophthalmology (OPH)
Respiratory Diseases (RD)
NIBR Platforms
Global Discovery
Chemistry
Developmental &
Molecular Pathways
Center for Proteomic
Chemistry
Biologics Center
Metabolism and
Pharmacokinetics
(MAP & DMPK)
Biomarker Development
Preclinical Safety
Translational Medicine
Scientific Operations
Research Focus at NIBR sites
United States
Cardiovascular & Metabolism
Infectious Diseases
Oncology
Ophthalmology
Musculoskeletal
Center for Proteomic Chemistry
Developmental and Molecular
Pathways
Global Discovery Chemistry
Biologics Center
Translational Sciences
IT Automation & Support
United Kingdom
Gastrointestinal
Respiratory
Global Discovery Chemistry
Translational Sciences
Switzerland
Neuroscience
Oncology
Autoimmunity, Transplantation &
Immunology
Center for Proteomic Chemistry
Global Discovery Chemistry
Biologics Center
Translational Sciences
China
Infectious Diseases
Oncology
Epigenetics
Chemistry
Translational Sciences
Japan
Translational Sciences
India
Translational Sciences
~110 postdocs in Basel,
Cambridge, East Hanover,
Emeryville, Horsham, Shanghai
Specific centers focus on
different disease areas and
several platforms
Extensive External Collaborations Enhance the PipelineJoint ventures in research, technology and therapeutic products
Academia
Almost 300 alliances with academic centers
Industry
More than 150 alliances with major biotech companies
Drug Discovery & Development Takes a Long Time
10’000 compounds in the beginning
1 new Medicine10 compounds in the clinic
Preclinical
Research
Clinical
Phase I
1’000 compounds in vitro testing
~14 years
Clinical
Phase II
Clinical
Phase IIIRegistration
Knowledge of mechanism
Unm
et M
ed
ical N
ee
d
NIBR’s Research Strategy
Basic
Research
X
Drug
Discovery
Science-Driven
Business
Rationale
Translation of the Genome to TherapeuticsDefining the key druggable nodes within the network
Genome
Human Disease
Pathways: Collections of Targets for Multiple Indications
Cancer (colon/breast)Tuberous sclerosis
Immune diseases,
Tx rejection
Vascular proliferation
(stent implant)
Retinitis pigmentosa
mTOR pathway
Departments currently with post-doc
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EMV NIBR Research Organization
NIBR SITE HEAD
Emma Lees
Cellular
Assays
Biological
Therapeutics
Cancer
BiologyProject
Mgmt.
Bio-
informatics
ONC HEAD
Emma Lees
125 FTE
Pharmacology
Protein
Sciences
Biochemical
Lead
Discovery
Structural
Chemistry
Chem-
informatics
MAP Medicinal
Chemistry
Medicinal
Chemistry
Medicinal
Chemistry
Computatl.
Chemistry
Analytical
Chemistry
GDC HEAD
Mike Dillon75 FTE
Emeryville is a Fully Integrated NIBR-Oncology Site
Target identification through early clinical trial
Small molecule and antibody therapeutics
10-12 drug development programs in addition to early discovery
| Presentation Title | Presenter Name | Date | Subject | Business Use Only19
D0 –
D2
PoC Outcome
sPoCLead Selection
D3 D4 &
PoC
Full
Dev
Drug Discovery Innovation Chain Development
CSP Initiation
1 Quelle: Bain 2003Target Selection,
Assay Development
&
HTS / Lead Selection
Lead
Optimization
Candidate
Selection
Process
Early Clinical
Safety
and EfficacyRegistrat
ion
Large Clinical
Trials
20 | Cancer Biology Organization | Chuck Voliva | January 16, 2009 | Business Use Only
Cancer BiologyWhat we do
Support the pipeline in three major area:
Target Identification
& Validation
Mechanistic
BiologyTranslational
Sciences
Cancer Drivers Amplicon
Discovery
SNP 6.0 across cancer cell lines
Identification of Oncogenes at Focal Amplified Chromosomal Region Found in Pancreatic cancer
Mentor: Albert Lai, Cancer Biology, ONC
Post-doc: Bosun Min| Presentation Title | Presenter Name | Date | Subject | Business Use Only21
Co-Amplified RegionCCNE1
30
00
+ P
rim
ary
Tu
mo
r &
Ce
ll lin
es
SNP 6.0 (CNV Analysis of Tumor Samples)
Coding genes
Novartis Cell Line Encyclopedia Cancer Targets Identification
Validation by TMA-FISH
Fine-mapping by qPCR
Identification of Amplicon
dependent gene by pool shRNA screen
Gain of function studies
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Understand the role for p90 S6 kinases in supporting an EMT
Which of the EMT characteristics is dependent on signaling via RSK?
Does an active K-Ras-driven EMT = an active B-Raf-driven EMT?
What happens to the dependency on RSK for this process in the face of additional pathway mutations as occur in tumors?
Thiery et al, CELL 2009
Mentor: A B Jefferson, Cancer Biology, ONC
Post-doc: TBD
23 | Presentation Title | Presenter Name | Date | Subject | Business Use Only
Matthew Holderfield: Molecular Mechanisms of KRAS Oncogene Dependence
Mentor: Tobi Nagel, Cancer Biology
Debbie Chang: Tumor-Associated Macrophages in Breast Cancer
Mentor: Dylan Daniel, Pharmacology
Prasenjit Mukherjee: Protein Family Modeling
Mentor: Eric Martin, Computational Chemistry
Jing Lu: Cancer dependency on survival signaling pathways
Mentor: Pablo Garcia
Bosun Min: ID of Oncogenes at Focal Amplifications in Pancreatic Cancer
Mentor: Alberta Lai, Cancer Biology
Meghna Das Thakur: Mechanisms of Resistance to Novel Kinase Inhibitors
Mentor: Darrin Stuart, Pharmacology
Current Emeryville Post-docs
Highly interactive working environment
State of the art facilities
NIBR Research Facility at EMV
| Presentation Title | Presenter Name | Date | Subject | Business Use Only24
All research departments centralized in one building
Objectives
Support the postdocs’ scientific and career development
Inform next generation of scientists of NIBR’s approach to drug discovery
Effectively partner with academic centers of excellence
2 application tracks:
NIBR Postdoctoral Fellowships
Presidential Postdoctoral Fellowships
NIBR Postdoctoral Program
NIBR Postdoctoral Fellowship
Proposal from
Disease Area/Platform
reviewed and approved
Candidate interviewed
and hired
NIBR Presidential Postdoctoral Fellowship
CV Review
~2 weeks Variable <4 weeks~3 – 4 weeks 8 - 12 weeks
• Outline project
• Identify academic mentor
1st Interview
EO
(phone)
2nd Interview
DA/Platform
(phone)
3rd Interview
DA/Platform
(on site)
Proposal
writing
Proposal
review
EO: Education Office
DA: Disease Area
3 years
Well-defined project proposal
Yearly progress reports
Scientific seminars: 2-3/week
Postdoctoral seminar series
Participation in scientific conferences
Annual Postdoctoral Retreat
Academic Mentor
NIBR Postdoctoral Training Program
Some Topics for Postdoctoral Research at NIBR
Autoimmunity: T cell activation, lymphocyte trafficking, Th17 cells
Biologics: metabolic stability of siRNAs
Chemistry: computer-aided drug design
Dev & Mol Pathways: CNS lipid storage, vascular biology
Gastrointestinal: gut epithelial function, sensory neurobiology
Infectious Diseases: pathogen-host interactions
Neuroscience: neurodegeneration; protein misfolding
Oncology: apoptosis, Raf/Ras/MAPK, bioinformatics tools
(Work) Life after a postdoc at NIBR
2007 - 2009 Alumni
Scientist - Novartis ~25%
Scientist – other pharma/biotech ~25%
Faculty – academic/research institute ~ 5%
Non-research (including Novartis) ~20%
Another postdoc position/transition to faculty ~10%
Other/unknown ~15%
What do we look for in postdoc candidates?
Solid scientific background in almost any area – molecular and cell biology, biochemistry, mouse models, etc.
Strong critical abilities
Scientific vision
Passion for science
Apply Online
http://nibr.com
=> Careers
=> Working at NIBR
=> Search for jobs, keyword “postdoc”
NIBR Postdoctoral Fellowship
Presidential Postdoctoral Fellowshiphttp://nibr.com
=> Careers
=> Postdoctoral positions
Please mention that you attended this presentation.
Challenges facing the pharmaceutical industry
Internal challenges
Organizational complexityand mindset
Advancing patent expiries
Identifying/understanding newtargets
Rising costs of research anddevelopment
Increasing complexity andbreadth of developmentprograms
External challenges
Public perception
Product safety concerns (FDA and public)
Aging population
Declining industry productivity
Scientific and technologicaladvances
Rise of generics and biotechs
Price control pressure frompayors
Parallel imports
R&D investment has increased by 80% while NME output has remained stationary
Data referenced to 2002 data
R&D spend is predicted to grow more slowly over the next 6 years (~2% pa)
NME = New Molecular Entity (both small molecule and biologics)Evaluate Pharma World report 2016
Sensitive Insensitive
What are the Molecular Mechanisms That Determine KRAS Oncogene Dependence?A Novartis Post-Doc Project in Cancer Biology
Post-Doc: Matthew HolderfieldMentor: Tobi Nagel
KRAS mutations occur in ~20% of NSCLC.
KRAS mutant cancers are frequently refractory to MAPK or PI3K inhibitors.
Use an shRNA screen to identify genes that determine sensitivity to KRAS suppression.
KRAS
PI3KRAF
Proliferation and Survival
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Mission: Support drug discovery with murine cancer models reflecting
target biology and addressing drug mechanism of action
Subcutaneous, orthotopic and metastatic tumor models
• ~100 tumor cell line models
• Primary human tumor model collection
Genetically engineered mouse models
• MMTV-PyMT mammary; K14-HPV16 cervical squamous cell carcinoma models; BRAF mutant melanoma model
Nude rat tumor models to estimate therapeutic index
• PK, PD, efficacy, and preclinical safety readouts
Pharmacodynamic measurements in tumors and normal tissues
• ELISA, Western blot, FACS, IHC (w/ Experimental Pathology)
Imaging
• Bioluminescence, fluorescence and ultrasound imaging
pERK1/2 PE
0
300
600
900
14 16 18 20 22 24 26 28Days Post Implant
Vehicle
RAF265
Mean
Tu
mo
r V
olu
me (m
m3)
0
300
600
900
14 16 18 20 22 24 26 28Days Post Implant
Vehicle
RAF265
Inhibition of p-ERK in rat PBMCs by MEK inhibitor BYQ738
PharmacologyWhat we do
Mechanisms of Resistance to Novel Kinase Inhibitors
Mentor: Darrin Stuart, Pharmacology, ONC
Post-doc: Meghna Das Thakur| Presentation Title | Presenter Name | Date | Subject | Business Use Only39
Transgenic and xenograft mouse models of human cancer to predict
mechanisms of drug resistance to kinase inhibitors in Novartis pipeline- In contrast to in vitro screens, selective pressure is applied at pharmacologically
relevant drug concentrations
Resistant Sensitive
Selection Validation Molecular Characterization
0.0001 0.001 0.01 0.1 1 10 1000
20000
40000
60000
80000
Drug Concentration (mM)
Mentor: Dylan Daniel (Pharmacology)
Postdoc: Debbie Chang
Project Overview:
• Rationale: Increased inflammation is correlated with decreased survival in breast cancer patients
• Goal: To identify the molecular pathways regulating pro-tumorigenic macrophage differentiation
• Model: Transgenic mouse model for breast cancer (MMTV-PyMT)
• Hypothesis: M-CSF/CSF1R pathway promotes pro-tumorigenic differentiation of tumor-associated macrophages(TAMs)
• Approach: Novartis has developed a highly selective CSF-1R inhibitor, BLZ945, that we are using to test howloss of CSF1R signaling affects the survival, recruitment and/or differentiation of TAMs [in collaboration with theCoussens Lab at UCSF]
Tumor-Associated Macrophages in Breast Cancer
Angiogenesis
Growth
Metastasis
EGF
Cancer cells
Pro-tumorigenic macrophages
Differentiation
Recruitment
Survival
M-CSF/CSF1R
BLZ945
41 | Presentation Title | Presenter Name | Date | Subject | Business Use Only
Matthew Holderfield: Molecular Mechanisms of KRAS Oncogene Dependence
Mentor: Tobi Nagel, Cancer Biology
Ting Gong: Computation Dissection of Tissue Samples with Applications to Complex Samples from Clinical Trials
Mentor: Joseph Szustakowski, Biomarker Development, Translational Sciences
Sonya Fonseca: Enhancement of β-cell Function through ER Stress Signaling Modulation
Mentor: Mark Burcin, Cardiovascular and Metabolism
Zachary Newby: Structure and Function of Intramembrane Proteases: The Rhomboid and SPP/SPPL Families
Mentor: Michael Romanowski, Center for Proteomic Chemistry
Nicolas Guérard: Characterization of specific patterns for Torsade de Pointes in isolated rabbit heart using transmural unipolar electrograms
Mentor: Berengere Dumotier, Preclinical Safety, Translational Sciences
Ken-Ichi Umehara: In vitro transporter assays and their use to understand hepatic and renal disposition of new drug candidates in clinics using PBPK techniques
Mentor: Gian Camenisch, DMPK, Translational Sciences
Current NIBR Post-docs