Targeting the mTOR/4E-BP Pathway in Endometrial CancerReview Targeting the mTOR/4E-BP Pathway in Endometrial Cancer Sharmilee Bansal Korets 1, Sarah Czok , Stephanie V. Blank 1,3,

Review

Targeting the mTOR/4E-BP Pathway in Endometrial Cancer

Sharmilee Bansal Korets1, Sarah Czok1, Stephanie V. Blank1,3, John P. Curtin1,3, and Robert J. Schneider2,3

AbstractEndometrial cancer is the most common gynecologic malignancy. Although it is highly treatable in the

early stages of disease, therapies for advanced and recurrent disease are rarely curative. A molecular and

genetic understanding of endometrial cancer involves the mTOR signaling pathway, an emerging target for

treatment of type I disease (the most common presentation). Endometrial cancers show a significant

reliance on themTORpathway for survival, and studies todatehave revealed a clinical advantage in targeting

this pathway. Lesswell developed in the study of endometrial cancer is an understanding ofmTOR signaling

to its major downstream effector, translational control. Given the poor rate of success for treatment of late-

stage endometrial cancer, increasing attention is being directed to the development of new therapeutic

approaches, including targeting the mTOR pathway. Here, we discuss the potential benefit of targeting

mTOR combined with existing chemotherapies by monitoring its impact on translational regulatory

pathways and key translation targets in endometrial cancer. We also highlight laboratory and clinical

research findings that will provide new avenues for future research and clinical development. Clin Cancer

Res; 17(24); 7518–28. �2011 AACR.

Introduction

Endometrial cancer is the most common gynecologicmalignancy and the fourth most common malignancy inAmerican women, with 43,470 new diagnoses and 7,950deaths for the year 2010 (1). Although themajority of endo-metrial cancers are diagnosed at an early stage of disease,conferring a favorable prognosis, women who are diag-nosed with advanced or recurrent disease have far worsesurvival rates and limited adjuvant treatment options. Inthe United States, �15% of endometrial cancers are diag-nosed at stage III or IV, with a 5-year survival rate of 20% to50% depending on grade and histologic subtype (2). Overthe past 30 years, little significant improvement has beenseen in the survival of patients with advanced disease (3).

Endometrial cancers are commonly classified into 2 his-tologic subtypes (4): endometrioid (type I) and nonendo-metrioid (type II). Each has distinct risk factors, clinicalbehaviors, and natural histories. Type I tumors are themostcommon (85%), primarily early stage at diagnosis in post-menopausal, obesewomenover the age of 50, and estrogen-dependent in a background of atypical hyperplasia. Type IIlesions (15%) are primarily comprised of serous and clear-cell histologies. Type II tumors are more aggressive and

associated with extrauterine spread, later-stage disease, andpoorer prognosis.

Type I and type II malignancies also have distinct molec-ular and genetic characteristics (5). Type I endometrialcancers exhibit a high frequency of microsatellite instabilityand loss-of-function mutations in the phosphatase andtensin homolog PTEN tumor-suppressor gene. Type II can-cers more frequently show p53 mutations.

Patients with advanced disease typically receive adjuvantchemotherapy [cisplatin–doxorubicin–paclitaxel (6)] withorwithout radiation after surgical staging. As a result of poortoxicity profiles, the molecular targets and signal transduc-tion pathways involved in endometrial cancer are nowunder investigation in multiple phase I and II trials (7).

Here, we focus on the role of mTOR inhibition in futuretreatment strategies and downstream effects on proteinsynthesis, with the goal of increasing new combinationtherapeutic approaches and the use of novel biomarkers toachieve better treatment response. Indirect (allosteric)mTOR inhibitors, known collectively as rapalogs, showactivity in the treatment of type I disease. Therefore, rapa-logs represent attractive investigational drugs for the man-agement of endometrial cancer due to their relationshipwith the PTEN signaling pathway, which is frequentlymutated in type I endometrial cancers. However, a newclass of catalyticmTOR inhibitors that act directly onmTORhave been introduced in phase I dose-escalation trials.These drugs more effectively inhibit mTOR in both of itssignaling complexes, mTORC1 and mTORC2. Taking intoaccount the emergence of direct mTOR inhibitors and thedeveloping knowledge about the effects of mTOR inhibi-tion on protein synthesis, we review the present under-standing of the role of the mTOR–translational control

Authors' Affiliations: Departments of 1Obstetrics and Gynecology and2Microbiology, and 3NYU Cancer Institute, New York University School ofMedicine, New York, New York

Corresponding Author: Robert Schneider, Department of Microbiology,NYU School of Medicine, 550 First Avenue, New York, NY 10016. Phone:212-263-6006; Fax: 212-263-8276; E-mail: [email protected]

doi: 10.1158/1078-0432.CCR-11-1664

�2011 American Association for Cancer Research.

ClinicalCancer

Research

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pathway in the etiology, progression, and treatment ofendometrial cancer.

Major Molecular Alterations in Type IEndometrial Cancer: A Brief Overview

The genes that are commonly mutated in type I endo-metrial cancers are largely responsible for the regulationof signal transduction, which is involved in normal cellreplication and cell–cell adhesion. Thus, disruption ofthese pathways and functions leads to abnormalities incell proliferation and to the ability to invade or metasta-size. The most frequent alterations in type I endometrialcancers are summarized in Table 1. Because this area hasbeen extensively reviewed in the past (8, 9), we provideonly a summary of key features that also affect mTORand translational regulation in this disease.

PTENThe most common genetic mutation in type I endo-

metrial cancers (83%) occur in the phosphatase genePTEN, with loss or mutation (8, 9). PTEN is a tumor-suppressor gene, the loss of which plays a major role instimulating the phosphoinositide 3-kinase (PI3K)–AKT–mTOR pathway (10). PI3K–AKT–mTOR upregulationmodestly upregulates protein synthesis and more stronglyupregulates translation of survival, angiogenesis, and so-called oncogenic mRNAs (ref. 11; Fig. 1).

PTEN has lipid and protein phosphatase activity(10, 12, 13). The lipid phosphatase domain maintainscell-cycle arrest at the G1–S checkpoint, upregulatesAKT-dependent proapoptotic pathways, and downregu-lates Bcl-2–dependent antiapoptotic pathways (14).PTEN controls the levels of phosphorylated AKT byopposing PIK3CA activity. The protein phosphatasedomain inhibits focal adhesion formation, cell spread-ing, and migration (15). Increased mTOR activation andprotein synthesis are necessary to sustain these activities(11). Studies of PTEN knockout mice have helped elu-cidate its role in endometrial cancer. In one study (16),100% of the mice examined developed hyperplasticlesions in the endometrium and 20% developed endo-metrial carcinoma as a result of heterozygous mutationsin PTEN.

PIK3CAThe PIK3CA gene encodes the a catalytic subunit of

PI3K. This lipid kinase catalyzes production of PIP3, result-ing in the activation of multiple downstream targets, mostnotably AKT, leading to mTOR activation, and thus pro-moting cell proliferation and survival (17). As noted above,this pathway is upregulated in a majority of endometrialcancers. Thirty-six percent of patients with endometrialcancer have PIK3CA mutations, and 26% have concurrentPTEN and PIK3CA mutations (18). PIK3CA mutations arestrongly associated with endometrioid histology and ahigher stage, and show a trend toward increased incidenceof lymphovascular invasion (19).

KRASThe KRAS gene is a proto-oncogene encoding a small

inner plasma membrane GTPase that is involved in cellsignaling related to growth and differentiation. KRASmutations resulting in constitutive activity are present in10% to 30% of type I endometrial cancers and 16% ofhyperplastic lesions. Similar to the PTEN mutation, thefrequency of the KRAS mutation is increased in endo-metrial cancers that show genomic instability (8, 9, 20).Additionally, KRAS mutations stimulate downstreammTOR kinase activity, leading to increased selective trans-lation of mRNAs involved in tumor cell survival, angio-genesis, and proliferation (11).

Mutation of the LKB1 geneLKB1 (also known as STK11) is a serine–threonine

kinase that phosphorylates and activates AMPK-dependent

Table 1. Molecular alterations in type Iendometrial cancer

Molecular alteration Frequency Reference

PTEN 50–83% Hecht and Mutter (8)PIK3CA 36% Liu et al. (80)b-catenin 20–40% Bansal et al. (9)K-ras 10–30% Hecht and Mutter (8)Microsatellite instability 20% Basil et al. (81)LKB1 20% Lu et al. (25)E-cadherin 10–20% Bansal et al. (9)p53 10–20% Bansal et al. (9)

Translational Relevance

Endometrial cancer remains the most common gyne-cologic malignancy. Although it is highly curable bysurgery when diagnosed at an early stage and grade, theburden of advanced stage and recurrent disease is sub-stantial. Current combination therapies are highly toxicand of limited efficacy for the treatment of patients whorequire systemic therapy. Advances in the moleculargenotyping of endometrial cancers have led to an intensefocus on molecularly targeted agents that act on themTOR pathway, and this approach has shown some ofthe best responses in the treatment of advanced andrecurrent disease. In this short review, we explore therelationship between endometrial cancer and themTORpathway and its downstream regulation of protein syn-thesis. We suggest that there is a critical need to matchexperimental mTOR therapeutics with existing chemo-therapies by optimizing the impact on translationalregulatory pathways in the treatment of endometrialcancer.

mTOR and Translational Regulation in Endometrial Cancer

www.aacrjournals.org Clin Cancer Res; 17(24) December 15, 2011 7519




kinase [AMPK (21)]. AMPK senses ATP–AMP levels, there-by regulating cellular metabolism (22). mTOR is inhibitedby active AMPK through phosphorylation and activationof the tuberous-sclerosis complex-2 (TSC2) protein, anupstream inhibitor of mTORC1 (ref. 23; Fig. 1). Thus,

mutation of LKB1, similar to mutation of PTEN or KRAS,and elevated levels of insulin-like growth factor I (IGF-I)results in strong mTOR activation and upregulation ofprotein synthesis. Animal models of LKB1 deficiency showa high level of aggressive features in endometrial cancers,

© 2011 American Association for Cancer Researchsociation for Cancer Research

AMPK

4E-BP

mLST8

4E-BP

PDCD4

eIF4E

eIF4A

eIF4F

eIF4G

eIF4E eIF4A

eIF4B

S6K

S6K

S6

P P

P

P

P

MEK

Raf

IRS

1Ras

PTEN

GβLRictor

PRAS40

GDPGTP

RHEB RHEB

mTOR

mTORC2

Receptortyrosine kinases

Plasmamembrane

mTORC1inhibition

Cap-dependenttranslation off

Cap-dependenttranslation on

Hyper-P 4E-BPHypo-P 4E-BP

mTORC1

PDK1

Akt

TSC1

TSC2

PI3K

ERK

RSK

mTORRaptor

Figure 1. Signal transduction pathways for translational control. PI3K–AKT–mTORC1 and Ras–MAPK pathways, as well as their targets involved intranslation initiation, are shown. Mitogenic signals (growth factors, cytokines, and hormones) act on receptor tyrosine kinases to stimulate Ras andPI3K. The activation of PI3K stimulates AKT, which inhibits TSC1–TSC2 GAP activity, allowing Rheb-GTP–mediated stimulation of mTORC1. Inaddition, AKT negatively regulates PRAS40, an inhibitor of mTORC1. The activation of mTORC1 may also be mediated by inhibitory phosphorylationof TSC1/2 complex by extracellular signal-regulated kinase (ERK) and p90RSK. PTEN, a phosphatase, opposes activation of mTORC1 by PI3K.Under hypoxia and low-ATP conditions, the activation of AMP kinase leads to mTORC1 inhibition. mTORC1 activity is, therefore, stimulated bymitogenic and growth-promoting signals and suppressed by growth-inhibiting signals. Activated mTORC1 phosphorylates the 4E-BPs, resulting ineIF4E dissociation from 4E-BPs and eIF4E interaction with eIF4G. In addition, mTORC1 stimulates eIF4B-enhanced eIF4A helicase activity through theS6K-mediated phosphorylation of eIF4B and PDCD4, an inhibitor of eIF4A. All of these events promote the assembly of the cap-binding complex eIF4F(composed of eIF4E, eIF4G, and eIF4A), stimulating cap-dependent translation. In contrast, downregulation of mTORC1 leads to decreasedphosphorylation of 4E-BPs and eIF4E sequestration, and inactivation of eIF4A, eIF4B, and eEF2, which results in reduced cap-dependent mRNAtranslation. MAPK, MAP kinase; MEK, MAP–ERK kinase; 4E-BP, eIF4E binding/inhibiting protein.

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Clin Cancer Res; 17(24) December 15, 2011 Clinical Cancer Research7520




consistent with elevated mTOR activity (24). Studies ofhuman endometrial tumors have shown that �20% areLKB1-negative, and as many as 65% have a functionaldeficit in the protein (25).

Elevated IGF-I levelsEndometrial cancers are associated with elevated IGF-I

expression and activation of the IGF-I signal transductionpathway (26). Whereas estrogen increases IGFI gene tran-scription (26), PTEN downregulates IGF-I receptor levels(27), which are typically increased in endometrial cancers(28). The IGF-I pathway thus links loss of PTEN,increased AKT–mTOR activation (29), and estrogensignaling in endometrial cancer. Recently, a direct linkwas established for the regulation of IGF-I and insulin bythe PTEN–AKT–mTOR axis through mTOR target proteinGrb10, which when phosphorylated is a negative regula-tor of insulin signaling and IGF-I (30, 31).

The Role of Hormones in EndometrialCarcinogenesis

Hormones act on the endometrium to modify the genet-ically predetermined risk of cancer. Estrogen and proges-terone have divergent and often opposing effects on theendometrium (8). Estrogen can promote cell proliferationand inhibit apoptosis, whereas progesterone can inhibitproliferation and promote apoptosis and involution (32).Increased proliferative activity can increase the rate ofrandom mutation, possibly accounting for some of thepotential carcinogenic effects of estrogen on the endome-trium. Further, by promoting cell proliferation, estrogencreates a selective advantage for PTEN mutant clones thathave escaped the usual proapoptotic, antiproliferativecheckpoints (32). In addition to opposing endometrial cellproliferation, progesterone further counteracts the effect ofestrogen by downregulating expression of the estrogenreceptor itself. Progestins therefore reduce the proliferativeadvantage of PTEN mutant cells, leading these clones toinvolute (8).

ThemTOR/4E-BP Translational Control Pathway

Growth factor stimulation and hormone receptor acti-vation, as well as cellular responses to nutrient status,hypoxia, and other physiologic and metabolic altera-tions, ultimately signal to the protein kinase mTOR(Fig. 1; ref. 33). mTOR is a member of the PI3K–AKTfamily, which promotes cell proliferation, survival, andangiogenesis (34). mTOR is a serine–threonine kinasethat acts on factors in the protein synthesis machinery,integrating signals from a variety of growth factors andnutrients to regulate key metabolic and macromolecularprocesses, including mRNA translation, cell motility, andribosome biogenesis. mTOR forms 2 different proteincomplexes, mTORC1 and mTORC2, that mediate verydifferent functions, in part through mRNA translationalcontrol.

mTORC1 is a protein complex that contains mTOR,regulatory-associated protein of mTOR (Raptor), G-pro-tein b-subunit-like protein/LST8 [GbL (33)], and proline-rich AKT substrate 40 kDa (PRAS40). Raptor recruitssubstrates to mTORC1 for phosphorylation, includingthe eIF4E binding/inhibiting protein (4E-BP, inhibitedby mTORC1 phosphorylation) and ribosomal proteinS6 kinases-1,2 (S6K-1,2). S6K-1,2 phosphorylates ribo-somal protein S6, initiation factor eIF4B (stimulating itsRNA binding activity and translation), tumor suppressorprotein PDCD4 (increasing initiation factor eIF4A acti-vity), and translation elongation factor eEF2 kinase,thereby inactivating the kinase, and in turn promotingeEF2 activity and elongation (Fig. 1).

The second mTOR complex, mTORC2, contains GbL,the protein rapamycin-insensitive companion of mTOR(Rictor), and mammalian stress-activated protein kinase(SAPK)–interacting protein [mSIN1 (35)]. Activation ofmTORC2 regulates cytoskeleton organization in responseto growth factors and leads to increased phosphorylation(activation) of AKT, which in turn is an upstream activatorof mTORC1 and protein synthesis (36). mTORC2 is gen-erally insensitive to inhibition by allosteric mTOR rapaloginhibitors such as sirolimus, but not to small-moleculecatalytic mTOR inhibitors. Of importance, rapalog treat-ment can actually stimulate AKT–mTOR through mTORC2activation (37–40), which has fueled interest in the clinicaldevelopment of small-molecule, catalytic-site mTORC1/2inhibitors.

Rapalog inhibition of mTORAmplification of PI3K–AKT, increased transcription, or

loss of regulatory control by mutation or deletion of regu-lators such as PTEN can result in mTOR activation. Loss ofPTEN is the primary means for maintenance of increasedmTOR activity in endometrial cancer (41), as supported byanimal studies (42). Analyses of human type I and type IIendometrial cancers have shown a compelling associationamong PTEN loss, increased mTOR activity, hyperpho-sphorylation (inactivation) of the translation inhibitor4E-BP1, increased cancer progression, and reduced survivalin type I disease (43). That said, overexpression of mTORitself in endometrial cancer as a means for increased mTORactivity is actually quite rare (�7% incidence) and may notcorrelate with disease progression, survival, or even sensi-tivity to mTOR inhibition (44). In principle, however, theoveractive PI3K–AKT–mTOR pathway in endometrial can-cer should provide an excellent target for treatment due toan increased requirement for mTOR activity and increasedsensitivity when inhibited.

Rapamycin was initially used as an antifungal agent andsubsequently was applied as an immunosuppressant fortissue transplant patients. First-generationmTOR inhibitors(also known as rapalogs) include sirolimus (rapamycin),temsirolimus, everolimus, and ridaforolimus. All of theseinhibitors are sirolimus analogues that were developed fororal or i.v. administration by derivatization of the C40hydroxyl group. They inhibit mTORC1 by acting on FK506






binding protein 12 (FKBP12), an intracellular receptor thatactivates mTORC1 through a mechanism that remainspoorly understood (35). Rapalogs insufficiently inhibitmTOR, with loss of S6K-negative regulation ofIRS-1, poor activation of the 4E-BPs, and little inhibitionof protein synthesis. Rapalogs used as single-agent inhibi-tors have also been linked to increased AKT activity dueto positive feedback regulation of AKT by mTORC2(37, 39, 40).

mTOR-mediated translational control and itsimplications in endometrial cancer

The initiation of mRNA translation is generally the rate-limiting step of protein synthesis. A number of featurescontribute to widely different rates of initiation on differentmRNAs, creating a scenario of scalable and remarkablyselective translation of different mRNAs in response tophysiologic signals (11). Cellular mRNAs contain a 50

inverted 7-methylguanosine cap that serves as the recogni-tion site for the translation initiation machinery. The cap isrecognized by initiation factor eIF4E, which in turn recruitsthe scaffolding protein eIF4G and the ATP-dependent RNAhelicase, eIF4A, that collectively comprise the factor eIF4F(45). eIF4F interacts with the multisubunit factor eIF3,which in turn recruits the 40S small ribosome subunit andthe complex containing the initiating methionyl-tRNA,eIF2, and GTP (Fig. 1).

mTOR plays a pivotal role in regulating translationinitiation through control of eIF4F. The majority ofmRNAs require cap recognition by eIF4E and assemblyof the cap-initiation complex to recruit ribosomes andinitiate translation. mTOR phosphorylation of the 4E-BPs(4E-BP1 is the major epithelial cell form) promotescap-dependent mRNA translation by inactivating theireIF4E-sequestering activity (46). mTOR also phosphory-lates the major form of eIF4G (eIF4GI). The function ofeIF4G phosphorylation is unclear, but it may stimulate astructural alteration that promotes greater translationof a subset of mRNAs (47). mTOR phosphorylationactivates S6K-1 and S6K-2, which promotes cancer pro-gression (11). In particular, S6K1 phosphorylation ofeIF4B stimulates eIF4A activity and translation (48).Although increased mTOR activity (34) and levels ofprotein synthesis are a hallmark of many human cancers,as are increased levels of eIF4E, eIF4GI, and several othertranslation factors (11), the selectively increased transla-tion of a specific group of mRNAs that encode proteinsinvolved in angiogenesis, survival, and oncogenic func-tions is thought to provide the rationale for targeting theincreased mTOR activity found in endometrial and othercancers.

Increased mTOR activation favors selective mRNAtranslation

Studies have shown that increasedmTOR activity and theincreased expression of eIF4E and eIF4GI primarily favorstrong, selectively increased translation of a subset ofmRNAs with extensively structured 50 untranslated regions

(50UTR) and/or low abundance or multiple upstream openreading frames (49, 50). In general,whenmRNAswith thesecharacteristics are increased in translation, they become keyplayers in cancer development, angiogenesis, survival, hyp-oxia responses, and disease progression (11). Examplesinclude mRNAs that encode proteins for survival (MCl1,survivin, XIAP, and Bcl2), cell-cycle progression (c-myc,ODC1, and cyclin D1), angiogenesis (VEGF-A and FGF2),and response to hypoxia (HIF1a), among others (11).Increased expression of eIF4E/eIF4GI and/or increasedavailability of eIF4E or eIF4A (through reduced antagonisticPDCD4 levels) are thought to promote greater unwindingby eIF4A of 50UTR structures and, therefore, to dispropor-tionately promote greater translation of these mRNAs. Thisin turn is associated with increased malignancy anddecreased survival in a variety of human cancers, includingendometrioid endometrial cancers (43). Increased expres-sion of eIF4E and/or eIF4GI or hyperphosphorylation of4E-BP1 by activated mTOR is similarly associated withhigher tumor grade and stage, cancer progression, andreduced survival in a number of human cancers (43). Ina recent study, elevated expression of eIF4E was observedin more than half of the type I endometrial cancers exam-ined,with the greatest expression found at stages III/IV (51),suggesting that these tumors have a greater sensitivitytomTOR inhibition. The underlyingmechanism is thoughtto be strongly increased translation of select mRNAs. Inthis regard, understanding the dependence of selectivelyincreased mRNA translation on increased mTOR/eIF4Eactivity in endometrial cancer provides a new paradigmfor the design of therapeutic clinical trials. As describedbelow, single-agent and MTD strategies for mTOR inhibi-tors fail to take advantage of a low-toxicity therapeuticwindow in which we might be able to achieve selectivetranslation inhibition of oncogenic mRNAs while largelysparing overall protein synthesis.

Preclinical studies of mTOR inhibition in endometrialcancers

Rapalog studies in endometrial cancer have focusedprimarily on expression of mTOR pathway proteins(44, 52–58) and cellular responses to mTOR inhibitors(25, 52, 59–62). Several groups have also investigated therole of small-molecule mTOR kinase inhibitors in endo-metrial cancer cell lines (59, 63) and the effects of mTORinhibitors on mouse models of endometrial cancer(3, 64–66).

In multiple studies, investigators have tested the correla-tion between themTOR pathway and the control of proteinsynthesis and the clinical behavior of endometrioid tumors.Activation of mTOR and phosphorylation of 4E-BP1 occurmore frequently in advanced-stage and high-grade endo-metrial tumors, respectively (52), associated with cancerprogression and reduced survival (43). Similarly, a trendtoward increased activation of the AKT–mTORpathwaywasfound in patients with progesterone-refractory endometrialhyperplasia (55). Increased signaling in breast cancersthrough hormone receptors has been linked to increased

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activation of mTOR and, by extension, protein synthesis(67). Surprisingly, however, 2 studies in endometrial cancerrevealed no statistically significant correlation betweenexpression or activity of the AKT–mTOR pathway andsurvival or clinical-pathologic characteristics, includingstage, grade, and lymph node involvement (44, 56).In tissue-cell culture studies, researchers have further

investigated the impact of mTOR inhibition by rapalogtreatment on biologic activities and tumor developmentusing endometrial cancer cell lines. Overall, the resultsindicate that rapalogs are more effective as cytostatic agentsthan as cytotoxic ones and that they have the ability topotentiate the effects of other cytotoxic chemotherapeuticdrugs, including cisplatin and paclitaxel (58–60). In addi-tion, cell culture studies have shown dose-dependentantiproliferative properties of rapalogs as single agents(52, 58, 59, 61, 62).Mirroring human studies, tissue culturestudies have shown contradictory results with regard tothe impact of PTEN status on rapamycin sensitivity(32, 40, 41, 43). Investigators have also examined rapalogtreatment in mouse models of endometrial hyperplasia,and they found that treatment with rapalogs reduced tumorburden, slowed progression of disease, and decreased theincidence of hyperplastic lesions in mice predisposed tohyperplasia (3, 64–66).

Current clinical trials of mTOR inhibitors inendometrial cancerIn a number of completed and ongoing phase I and II

trials, researchers have investigated the role of oral andparenteral rapalogmTOR inhibitors in advanced and recur-rent endometrial cancers (7, 68). All rapalogs, whetheradministered by oral or i.v. routes, provide similar lowbiologic exposure and have been shown to inhibit thephosphorylation of 4E-BP1 or S6K1 as surrogate markersof activity in tumor specimens or circulating peripheralbloodmononuclear cells (69). Plasma concentrations showa prolonged half-life for sirolimus (�50 hours) comparedwith temsirolimus (�15 hours), which is converted tosirolimus (70). Using preclinical studies and demonstratedactivity in other malignancies as a reference, investigatorsare developing new regimens with the goal of achievingmore tolerable, efficacious treatments for advanced orrecurrent endometrial cancer.Studies have shown a variable response to mTOR

inhibition in the treatment of advanced and recurrentendometrial cancer. Treatment-na€�ve endometrial cancersshowed some of the highest objective response rates tosingle-agent mTOR inhibitors, second only to lympho-mas (71). Response rates in previously treated endome-trial cancers were also encouraging (72). Most of thesestudies, however, included varied patient populationswith endometrial cancers of different histologies anddiverse numbers of prior cytotoxic or hormonal treatmentregimens. Collectively, these studies showed responserates from 7% to 25%, with up to 57% of patientsachieving stable disease, i.e., potential clinical benefit(71, 73). One study with a 20-week follow-up, limited

to patients with endometrioid histology, showed a 21%stable disease rate at 20 weeks (74). A recent single-agentphase II study of temsirolimus showed a strong response(>80% stable disease) with long duration in chemother-apy-na€�ve women with recurrent or metastatic endome-trial cancer, compared with 50% in women with priorchemotherapy treatment (75). There was no correlationwith PTEN status. These data suggest that we have a realopportunity to inhibit mTOR as a first-line treatmentfor endometrial cancer by using judicious combinationsthat capitalize on biologic synergies other than PTENstatus and by exploiting combinations with other che-motherapeutics to maximize tumor cell killing andantiangiogenesis.

A significant untapped opportunity exists in the devel-opment of activity markers in the mTOR translationalcontrol pathway (76), focusing on highly mTOR-depen-dent oncogenic and survival mRNAs as biologic surrogatemarkers for treatment sensitivity and response. Clinicaltrials have produced conflicting results regarding whethermTOR or S6K phosphorylation (activity) correlates withtreatment response, mirroring preclinical studies (71, 74).Clearly, there is a need to develop better biomarkers ofmTOR sensitivity and endometrial cancer response, as wellas treatment strategies that build on the molecular bio-logic understanding of selective translation inhibitionby mTOR interference. Investigators need to reexaminethe important issue of rapalog toxicity as currently con-figured in clinical use. It is unknown whether present levelsof treatment efficacywill bemaintained at lower dose levels.The fact that biologic exposure (i.e., plasma concentrationover time) does not proportionally increase with dosemay indicate that higher or more frequent dosing near theMTD merely increases toxicity, with little if any gain inantitumor activity and survival. A more fruitful approachmight be to focus on achieving better synergy based onbiologic activities with conventional chemotherapeutics,rather than on the MTD. In this regard, temsirolimus andeverolimus are used at slightly lower levels than the MTD,whereas sirolimus is used at the MTD. Toxicities in clinicaltrials have included dyslipidemia, mucositis, myelo-suppression, fatigue, infections, and pneumonitis. In aphase I trial of temsirolimus in combination with topo-tecan for advanced or recurrent gynecologic malignancies,the dose-limiting toxicity was myelosuppression, and theregimen was intolerable in women who had previouslyreceived radiation (77). Researchers have now completedor are conducting more than 10 early-phase clinical trialsof rapalogs in patients with endometrial cancer to furtherinvestigate response, active combinations, and toxicities.The outcomes and biomarkers of these trials are beingevaluated, and available results are summarized in Table 2.Overall, it is likely that intermittent rather than daily dosingwill provide lower toxicity while preserving antitumoractivity (34). These trials give investigators the ability toevaluate both retrospectively and prospectively treatmentresponse with potential biomarkers based on translationalcontrol and translation targets of mTOR activity.






Table 2. Completed and ongoing phase I and II studies of mTOR inhibitors in endometrial cancer

Study name Summary Status Findings Reference

Carboplatin–paclitaxel–ridaforolimus in endometrial,ovarian, and solids

Phase: IB Approved,not yetactive

N/A N/AAssessment: MTD of ridaforolimus

(rapalog) in combination withcarboplatin–paclitaxel

Population: metastatic/recurrentendometrial cancer, up to 1 priorchemotherapy regimen

BEZ235 trial in patientswith advanced endometrialcarcinoma

Phase: II Approved,not yetactive

N/A N/A

Assessment: safety and activityof BEZ235 (dual P13K–mTORinhibitor)

Population: recurrent or progressiveendometrial carcinoma after first-line treatment

Study of the combination oftemsirolimus and pegylatedliposomal doxorubicin inadvanced or recurrent breast,endometrial, and ovarian cancer

Phase: I Active N/A N/AAssessment: combination of

temsirolimus (rapalog) and PLDPopulation: advanced/recurrent

breast, endometrial and ovariancancer

Phase II study of Akt inhibitorMK2206 in patients with PIK3CAmutation recurrent or advancedendometrial carcinoma

Phase: II Active N/A N/AAssessment: activity of MK2206

(Akt inhibitor)Population: recurrent/persistent

endometrial cancerBiomarkers: PIK3CA mutation

Study of weekly oral RAD001in combination with oraltopotecan in patients withadvanced or recurrentendometrial cancer

Phase: I Active N/A N/AAssessment: activity of topotecan

and RAD001 (rapalog)Population: advanced/recurrent

endometrial cancerBKM120 as second-line therapyfor advanced endometrial cancer

Phase: I Active N/A N/AAssessment: activity of BKM120

(PI3K inhibitor)Population: recurrent endometrial

cancer,Biomarkers: PI3K activation status

Safety study of XL147 incombination with paclitaxel andcarboplatin in adults with solidtumors

Phase: I Active N/A N/AAssessment: safety and tolerability

of XL147 (PI3K inhibitor)Population: solid tumors, including

advanced/recurrent endometrialcancer

Letrozole and RAD001 in advancedor recurrent endometrial cancer

Phase: II Active N/A N/AAssessment: activity and safety

of RAD001 and Femara (letrozole)Population: recurrent/progressive

endometrial cancer.

(Continued on the following page)

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Table 2.Completed and ongoing phase I and II studies of mTOR inhibitors in endometrial cancer (Cont'd )

Study name Summary Status Findings Reference

Phase II study of temsirolimusand bevacizumab in patients withlocally advanced, recurrent,metastatic, or progressiveendometrial, ovarian epithelial,hepatocellular, islet cell, orcarcinoid cancers

Phase: IIAssessment: tolerability and activity

of temsirolimus and bevacizumab(anti-VEGF antibody)Population: multiple solid tumors

Active N/A N/A

Molecular correlates associatedwith a phase II study oftemsirolimus (CCI-779) in patientswith metastatic or recurrentendometrial cancer (NCIC IND160)

Phase: IIAssessment: activity of temsirolimus

Population: chemotherapy-naïve,recurrent/metastatic endometrialcancer

In progress 26% partial response,63%stable disease;responsesirrespective ofPTEN status

Oza et al. (71)

Biomarkers: PTEN statusPhase II trial of the mTORinhibitor AP23573 as a singleagent in advanced endometrialcancer (NCIC IND 148)

Phase: IIAssessment: response to

AP23573 (ridaforolimus)Population: progressiveendometrial cancer, up to 2 priorchemotherapy regimens

In progress 33% stable disease,partial or completeresponse; 52%discontinuedtreatment before4 cycles due toprogression

Columboet al. (73)

Phase II study of the oralmammaliantarget of rapamycin inhibitor,everolimus, in patients withrecurrent endometrial cancer

Phase: IIAssessment: response and toxicities

of everolimusPopulation: pretreated, recurrent,endometrioid endometrial cancer

Completed No partial or completeresponses; 21%stable disease at 20weeks;49%requireddose reduction tohalfstartingdosedueto toxicity

Slomovitzet al. (74)

Phase I studyofweekly temsirolimusand topotecan in the treatment ofadvanced and/or recurrentgynecologic malignancies

Phase: IAssessment: tolerability of weekly

topotecanwithweekly temsirolimusPopulation: recurrent gynecologicmalignancies not responsive tostandard therapy

Completed DLT for thecombination wasmyelosuppression;patients with historyof pelvic RT couldnot receive fulldoses of each agentin combination;82% had stabledisease at firstevaluation

Temkin et al.(77)

Phase II study of temsirolimus inwomen with recurrent ormetastatic endometrial cancer; atrial of the NCIC group

Phase: IIAssessment: response and toxicityof single-agent temsirolimusPopulation: chemotherapy-naïve orpreviously treated recurrent ormetastatic endometrial cancerBiomarkers: PTEN status

Completed Naïve patients: 14%partial response,69% stable diseaseat 5 months and 9months,respectively.Previously treatedpatients: 4% partialresponse, 48%stable disease at�4months. Nocorrelation withPTEN status.

Oza et al. (75)

Abbreviations: DLT, dose-limiting toxicity; N/A, not applicable; NCIC, National Cancer Institute of Canada; PLD, phospholipase D; RT,radiotherapy.






Future Directions: The Difficulty of TargetingmTOR and Translational Control

A significant problem in targeting mTOR withrapalogs is that these agents show partial inhibitoryactivity. They only moderately block mTORC1 andhave little (if any) effect on mTORC2, thereby increas-ing AKT activity (37, 39, 40). It is unlikely that wecan overcome this obstacle therapeutically by conti-nuous rapalog exposure, which is reported to inhibitmTORC2 (78), because such an approach would re-quire a dose that is not clinically sustainable. This issuemay be obviated by the development of mTORC1/2active-site catalytic kinase inhibitors that more stronglyblock S6K and 4E-BP phosphorylation and mTORC2activity and consequent upregulation of AKT activity,and thus would likely provide greater therapeutic ben-efit. Preclinical studies in a murine B-cell lymphomamodel suggest a particular synergy for tumor cell kill-ing with mTORC1/2 inhibition in the setting of hyper-activated eIF4E (79). This may be particularly relevantfor the majority of endometrial cancers in which eIF4Eis overexpressed. On the other hand, preclinical and

clinical trials to date have only begun to capitalize onthe ability to synergize additional chemotherapies withpartial mTORC1 inhibition, such as addition of ERKinhibitors. Further study of the rapalogs in combina-tion with traditional cytotoxic agents, as well as themore-specific small-molecule mTOR kinase inhibitors,is therefore warranted.

Disclosure of Potential Conflicts of Interest

R.J. Schneider is a consultant to PTC Therapeutics, Inc., CelgeneCorporation, and Eli Lilly/ImClone companies. S.V. Blank, J.P.Curin, S.B. Korets, and S. Czok disclosed no potential conflicts ofinterest.

Grant Support

Department of Defense Breast Cancer Research Program, Breast CancerResearch Foundation, and Avon Breast Cancer Foundation (R.J. Schneider);Ortho Biotech Gynecologic Oncology Fellowship Program Grant (S.V.Blank, J.P. Curin, and S. Czok).

Received June 28, 2011; revised October 4, 2011; accepted October 10,2011; published OnlineFirst December 5, 2011.

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Targeting the mTOR/4E-BP Pathway in Endometrial CancerReview Targeting the mTOR/4E-BP Pathway in Endometrial Cancer Sharmilee Bansal Korets 1, Sarah Czok , Stephanie V. Blank 1,3,