Endometrial Cancer SPORE
The University of Texas MD Anderson Cancer Center
Principal Investigator(s):
Karen H. Lu, MD
Russell R. Broaddus, MD, PhD
- Principal Investigator(s) Contact Information
- Overview
- Project 1: Novel Targeted Strategies for Prevention and Conservative Management of Complex Atypical Hyperplasia and Grade 1 Endometrioid Endometrial Cancer
- Project 2: CTNNB1 Mutation and Wnt Pathway Activation Define Clinically Aggressive Endometrioid Endometrial Carcinoma
- Project 3: EphA2 Targeting in Uterine Carcinoma
- Project 4: A Framework for Identification of Novel Targeted Therapy Combinations in Endometrial Cancer
- Administrative Core
- Pathology Core
- Biostatistics and Bioinformatics Core
- Developmental Research Program
- Career Enhancement Program
Principal Investigator(s) Contact Information
Karen H. Lu, MD
Professor and Chair
Department of Gynecologic Oncology
University of Texas
MD Anderson Cancer Center
1515 Holcombe Boulevard, Unit 1362
Houston, TX 77030
Tel: (713) 745-8902
Russell Broaddus, MD, PhD
Professor and Chair
Department of Pathology & Laboratory Medicine
University of North Carolina School of Medicine
Campus Box #7525, Brinkhous-Bullitt Building
Chapel Hill, NC 27599
(919) 966-4676
Overview
The overall goal of the Endometrial Cancer SPORE at MD Anderson Cancer Center is to conduct highly innovative translational research for the prevention and treatment of endometrial cancer. Encompassed within this broad overall goal are the following more specific goals: 1) develop novel therapeutic strategies for advanced/recurrent endometrial cancer and aggressive subtypes; 2) promote novel strategies for unmet clinical needs in prevention and conservative therapy of high-risk precancerous lesions and low grade endometrial cancer; 3) incorporate molecular diagnostics into clinical decision-making; and 4) recruit and support new investigators in endometrial cancer research through the Career Enhancement and Developmental Research Programs. Over the last 5 years, our SPORE has led the field with a highly productive translational research team that has helped to define the clinical and molecular heterogeneity of endometrial cancer. This proposal includes 4 translational research projects addressing scientific problems that span the breadth of endometrial cancer heterogeneity in an effort to impact as many patients as possible.
Project 1, “Novel Targeted Strategies for Prevention and Conservative Management of Complex Atypical Hyperplasia and Grade 1 Endometrioid Endometrial Cancer,” includes a phase II trial using the mTOR inhibitor everolimus to improve standard conservative therapy (progestin-eluting intrauterine device) and is paired with innovative molecular profiling and pharmacologic approaches to further advance conservative treatment options.
Project 2, “CTNNB1 Mutation and Wnt Pathway Activation Define Clinically Aggressive Endometrioid Endometrial Carcinoma,” focuses on targeted therapeutics and molecular mechanisms underlying a clinically aggressive subtype of endometrioid endometrial cancer that is driven through beta-catenin mutation and downstream Wnt pathway activation.
Project 3, “EphA2 Targeting in Uterine Carcinoma,” focuses on the therapeutic target, EphA2. EphA2 is overexpressed especially in higher grade endometrioid carcinomas and in serous carcinoma and is associated with poor overall survival. A phase I clinical trial will evaluate the efficacy and toxicity of a novel therapeutic (EPHARNA) that targets EphA2 by delivering short interfering RNA into tumor cells via a neutral liposome nanovehicle. This therapeutic was developed by Project 3 investigators.
Project 4, “A Framework for Identification of Novel Targeted Therapy Combinations in Endometrial Cancer,” will evaluate tumor molecular changes from samples procured during a combinatorial trial of PARP and PI3K pathway targeted therapy to identify biomarkers of benefit for patients with endometrial cancer. This is paired with implementing a platform to evaluate mechanisms responsible for adaptive resistance to targeted therapies in order to enable a rational design of improved combination therapies.
Four interactive Core resources “Administrative Core, Pathology Core, Biomarkers Core, and Biostatistics and Bioinformatics Core,” support these projects and also enhance the infrastructure for translational research in endometrial cancers.
Project 1: Novel Targeted Strategies for Prevention and Conservative Management of Complex Atypical Hyperplasia and Grade 1 Endometrioid Endometrial Cancer
Project Co-Leaders:
Karen H. Lu, MD (Clinical)
Samuel C. Mok, PhD (Basic)
High-risk precancerous lesions (complex atypical hyperplasia, CAH) and grade 1 non-invasive endometrioid endometrial cancer (EEC) are typically treated by total hysterectomy and bilateral salpingo-oophorectomy; however, there is an increasing need for conservative treatment. Conservative therapy is particularly important for two groups of patients, 1) morbidly obese women with high surgical risks, and 2) premenopausal women who wish to maintain fertility. In fact, the Gynecologic Cancer InterGroup has recently identified conservative therapy for these patients as a key unmet clinical need that should be prioritized for research. Moreover, these two groups make up a significant portion of EEC patients. Obesity is a strong risk factor for EEC, and it is estimated that 12-17% of women with EEC are morbidly obese, with this percentage likely to increase as the obesity epidemic continues. In addition, approximately 20% of EEC cases occur in premenopausal women, for whom fertility-preservation may be desired.
Progesterone is known to counteract the effects of estrogen in the endometrium, and our studies have shown that a progestin-eluting intrauterine device (levonorgestrel IUD) is effective against over 80% of CAH, but only 50% of grade 1 cancers respond. Preclinical studies and clinical trials in recurrent EEC have shown that mTOR inhibition (via everolimus) in combination with blocking estrogen signaling may further improve response rates. We will conduct a phase II clinical trial of levonorgestrel IUD alone or in combination with oral everolimus. We predict that targeting this dual pathway approach will significantly improve clinical responses in early EEC. We will then leverage advanced molecular profiling technologies using microdissected stromal and epithelial components of endometrial tissue samples to identify aberrations that are associated with levonorgestrel IUD-responsive CAH and grade 1 disease versus levonorgestrel IUD-resistant disease (including subgroups of everolimus responders and everolimus non-responders). Our studies will also evaluate endometrial stroma-gland crosstalk signaling in treatment response. These highly translational studies will define profiles for high-risk subgroups that warrant combination treatment with everolimus and potentially identify additional molecular targets for future studies focused on cancer prevention and therapeutics. Our overall goal is to ensure that conservative management is an effective and feasible clinical option. For this reason, we are developing and optimizing a polymer-based intrauterine drug delivery system to improve tolerability of conservative therapy. We propose that intrauterine drug delivery can enable long-term sustained intrauterine administration of everolimus without toxicities related to systemic administration. Overall, this project uses the combined expertise of clinical and basic science research to rapidly advance translational studies to improve clinical approaches to conservative therapy in CAH and grade 1 EEC.
Project 2: CTNNB1 Mutation and Wnt Pathway Activation Define Clinically Aggressive Endometrioid Endometrial Carcinoma
Project Co-Leaders:
Russell Broaddus, MD, PhD (Clinical) (University of North Carolina, Chapel Hill)
Wei Zhang, PhD (Basic) (Wake Forest University)
Endometrioid-type endometrial carcinoma (EEC) accounts for approximately 75% of all endometrial carcinomas, the fourth most common cancer in women in the US. Many patients with early stage and low grade EEC will be cured by surgery alone but for women who present with higher grade, advanced stage EEC, more aggressive therapeutics are needed to control the disease. From TCGA data (and validated from our own patients) we have identified four transcriptome subtypes of EEC with distinct clinicopathologic characteristics and mutation spectra. Cluster II consists of younger, obese patients with low grade EEC yet diminished survival. Although the Cluster II tumors had the lowest overall mutation rate, CTNNB1 exon 3 mutations were very common. These mutations were associated with activation of the Wnt/b-catenin signaling pathway. We hypothesize that mutations in exon 3 of CTNNB1 reprogram the molecular landscape leading to clinically aggressive EEC. Understanding of these mutations will better inform specific strategies targeting the Wnt pathway including cyclin D and CDK4. The following specific aims are proposed to test this hypothesis.
Aim 1. Test the hypothesis that exon 3 mutations of CTNNB1 alter cellular epigenetic programs, thus suppressing the hormonal gene expression program and activating a mesenchymal/neuronal and immunosuppressive gene expression programs. 1.1. Functionally characterize the 7 hot spot mutants by establishing isogenic stable lines expressing each of the mutants. 1.2. Characterize the regulatory network of mutant CTNNB1 by transcriptome and miRNA profiling of the stable lines and identify the target genes, initially focusing on ESR1, PGR, N-cadherin, PDGFA, WNT5A, WNT5B, IL-10, and TGFB2. 1.3. Determine the possible driver effect of N-cadherin, WNT5A, and WNT5B by gain of function or loss of function via siRNA (individually or in combinations) and examining relevant in vitro cellular endpoints.
Aim 2. Establish preclinical and clinical models to test the hypothesis that activating mutations of CTNNB1 are important drivers of tumorigenesis. 2.1. Evaluate the effects of CTNNB1 mutation in vivo. 2.2. Utilize a 3D in vitro system to test alternative therapeutics targeting Wnt/Β-catenin signaling. 2.3. Determine if CTNNB1 mutation promotes the formation of an immunosuppressive microenvironment in hysterectomy specimens.
Aim 3. Conduct a phase II, single arm therapeutic trial of ribociclib (Novartis CDK4/6 inhibitor), letrozole, and everolimus for advanced/recurrent EEC. We have previously shown that letrozole+everolimus is effective in a subset of these patients. Cyclin D1 is one of the highest induced proteins in CTNNB1-mutated endometrial carcinomas, and it interacts with CDK4/6 to promote cell cycle progression. We hypothesize that patients with carcinomas with CTNNB1 mutation will have higher expression of Cyclin D1 and therefore be more responsive to treatment with this combination. The trial will be enriched for patients with tumors with CTNNB1 mutations.
Project 3: EphA2 Targeting in Uterine Carcinoma
Project Co-Leaders:
Anil Sood, MD (Basic)
Robert L. Coleman, MD (Clinical)
Growing evidence suggests that EphA2 is an important therapeutic target in uterine cancer. Our recent integrative analysis of TCGA data further indicate that EphA2 upregulation is significantly correlated with poor survival. EphA2 is also expressed at high levels in the tumor vasculature and plays a critical role in regulating angiogenic functions. These findings, coupled with the low or absent expression of EphA2 in most normal adult tissues, make it a highly attractive therapeutic target. Despite its clinical benefit in patients with recurrent uterine cancer, dasatinib can result in substantial toxicity when combined with chemotherapy due to its “off-target” engagement. Therefore, more specific therapeutic approaches for targeting EphA2 are needed. To achieve this goal, we have focused on systemically delivered short interfering RNA (siRNA) against EphA2 (EPHARNA) using a neutral nanoliposomal platform. Our overall hypotheses are that 1) EphA2 gene silencing using EPHARNA enhances the therapeutic response selectively in CAV1 overexpressing tumors; 2) Inhibition of MEK signaling increases the sensitivity to EphA2-targeted therapy in uterine cancer. The overall goal of this renewal proposal is to use EPHARNA for selective EphA2 targeting in uterine carcinoma and determine the underlying mechanisms of response and adaptive changes. The proposed Aims are complementary and will be pursued in close collaboration with the Cores.
Project 4: A Framework for Identification of Novel Targeted Therapy Combinations in Endometrial Cancer
Project Co-Leaders:
Gordon B. Mills, MD, PhD (Basic) (Oregon Health and Science University)
Shannon N. Westin, MD (Clinical) (MD Anderson Cancer Center)
Endometrial cancer (EC) is the most frequent gynecologic malignancy and the fourth most common cancer among women in the United States. Although cure is possible for early disease, outcomes for patients with metastatic or recurrent disease have not improved significantly over the last two decades. Based on extensive characterization by our team and The Cancer Genome Atlas, EC has a high frequency of aberrations in targetable pathways including the phosphatidylinositol 3 kinase (PI3K, 92%), ARID1A (33%), and homologous recombination (HR 22% core and 77% extended members) pathways. However, to date, targeted monotherapies have not had a major impact in EC. Thus, how to leverage the therapeutic opportunities in EC represents a major gap in knowledge that represents the overarching goal of this application. Our overall goal is: to design and implement rational combination therapy clinical trials based on high quality clinical and preclinical data and models to improve outcomes for EC patients.
Aim 1. To identify and refine biomarkers of benefit in a combination trial of PARP and PI3K pathway targeted therapy in EC: Based on the underlying mutational aberrations present in EC, we are actively enrolling on the first information-rich, biopsy-embedded investigator-initiated trial targeting two nodes in the PI3K pathway (mTOR (2 dose schedules) and AKT) in combination with an effective “trapping” PARP inhibitor, olaparib. We will test the hypothesis that combined targeting of key nodes in the PI3K pathway and PARP inhibition will demonstrate benefit in EC patients. Extensive characterization of pre- and post-treatment biopsies at the DNA, RNA and protein levels will facilitate the identification of biomarkers of benefit including our current suite of biomarkers of responsiveness to PARP and PI3K pathway inhibitors. This is a unique approach and opportunity, supported by our evidence that PI3K and HR pathways aberrations are extremely common in EC, likely rendering patients sensitive to combined PI3K and PARP pathway inhibition.
Aim 2. To establish a preclinical framework to identify rational combination targeted therapies for EC to be evaluated in future EC clinical trials: Emergence of adaptive resistance to targeted therapies contributes to the lack of efficacy of monotherapy. We have used our Combinatorial Adaptive Resistance (CART) platform to identify a limited number of potential additional rational combinations for validation, aimed at adaptive resistance induced by targeting the DNA damage response. This Aim will focus on in vitro and in vivo preclinical data and biomarkers to prioritize combinations in future trials. To rapidly translate these rational drug combinations to clinical trials in this SPORE, AstraZeneca has signed a contract to provide funding for EC clinical trials with their complete therapeutic pipeline.
Administrative Core
Project Co-Leaders:
Karen H. Lu, MD (University of North Carolina, Chapel Hill)
Russell Broaddus, MD, PhD (MD Anderson Cancer Center)
The overall goal of the Endometrial Cancer SPORE at MD Anderson Cancer Center is to conduct highly innovative translational research for the prevention and treatment of endometrial cancer. To ensure the success of the SPORE, the Administrative Core will provide scientific oversight, as well as effective management and administration of all activities relating to each Project, Core, and Developmental Research/Career Enhancement Program in the SPORE. The Administrative Core will actively work to communicate and disseminate information within our internal SPORE investigators as well as facilitate information sharing and collaborations with other SPOREs and external constituencies. The Core will provide a structure to integrate diverse scientific disciplines into a unified multidisciplinary approach for achieving excellence in translational endometrial cancer research. Importantly, the Administrative Core will monitor timelines and ensure both basic science and clinical trial aims are met for all SPORE projects. The objectives of the Core are to 1) oversee all SPORE activities, including Projects and Cores; 2) provide administrative support for the DRP and CEP; 3) convene all meetings of the SPORE Executive Committee (all Program Co-leaders and Core Co-directors), Internal/External Advisory Committees, and Advocate Advisory Committee; 4) schedule all scientific meetings; 5) coordinate data quality control and quality assurance issues in collaboration with the Biostatistics and Bioinformatics Core, Pathology Core, and Biomarkers Core; 6) monitor and oversee all fiscal and budgetary issues; 7) interface closely with the other oversight committees related to endometrial cancer research at our institution, including the Gynecological Oncology Tumor Bank Oversight Committee; 8) maintain communication and coordinate research among investigators, as well as with other translational researchers, gynecologic cancer SPOREs, the Gynecologic Oncology Group, and SPOREs from other disease sites by distributing materials, electronic communications, and progress reports; 8) communicate with the NCI Project Officer and other staff to prepare all required reports and publications; 9) notify the NCI Project Officer promptly of important developments that affect the management of the SPORE either positively or negatively; 11) assure compliance with all general, governmental, and NCI regulations and requirements; and 12) establish and implement policies for recruitment of women and minorities. Dr. Karen Lu, Director of the Administrative Core and Co-Principal Investigator for the overall SPORE, will direct these activities with the assistance of the Co-Director of the Administrative Core and Co-Principal Investigator for the overall SPORE, Dr. Russell Broaddus.
Pathology Core
Core Director:
Russell Broaddus, MD, PhD
The individual research projects comprising this Endometrial Cancer SPORE proposal require the procurement, processing, and analysis of histopathological material from patients with endometrial cancer, the precursor lesion endometrial complex hyperplasia with atypia, and benign endometrial samples. The research projects have needs for frozen and formalin-fixed, paraffin-embedded samples of tumor and normal tissue. The proposed Pathology Core augments the already established M.D. Anderson Cancer Center Gynecological Tumor Bank and the P30 sponsored M.D. Anderson Cancer Center Centralized Tissue Repository with supporting database and intranet access. The Core provides for tissue, blood, and urine acquisition by experienced gynecological pathologists and research assistants to assure high-quality tissues and fluids for the investigators participating in this SPORE as well has investigators of other SPOREs.
The goal of the Pathology Core is to provide frozen tissue, paraffin-embedded tissue, and histopathological expertise related to the specific needs for the research projects comprising this SPORE proposal. To achieve this goal, the Pathology Core proposes the following Specific Aims. These aims remain unchanged since the previous Endometrial Cancer SPORE renewal. Aim 1 is to maintain a frozen and paraffin-embedded tissue repository of endometrial cancers, hyperplasias, and normal endometrial samples. The primary tissue sources will be operative and biopsy specimens submitted to the Department of Pathology at M.D. Anderson Cancer Center and a few SPORE-sponsored clinical trials. Aim 2 is to provide pathological review for all clinical specimens utilized in the SPORE projects and for related clinical trials and to provide histopathological technical services as necessary. Such technical services include immunohistochemistry, in situ hybridization, creation of specific tissue microarray slides, pathological evaluation of mouse tumors, and microdissection of tissue sections. Aim 3 is to establish a blood/urine/ascites fluid collection from patients undergoing hysterectomy for endometrial cancer and endometrial hyperplasia and from patients undergoing hysterectomy for non-endometrial pathology (uterine leiomyomas, cervix dysplasia, endometriosis). These fluids provide for the systemic application of biomarkers identified from tissue-based studies; such biomarkers may potentially be useful clinically for early diagnosis of endometrial cancer, biomarkers of endometrial cancer risk, or biomarkers of tumor recurrence. Aim 4 is to create and maintain a database for all frozen and paraffin-embedded endometrial tissues and fluids collected by the Core. This SPORE Database will provide for a virtual tissue repository that can be electronically shared with all SPORE investigators.
Biostatistics and Bioinformatics Core
Core Director:
Ying Yuan, PhD
The Biostatistics and Bioinformatics Core for the Endometrial Cancer SPORE program will support the Projects, and assist the other Cores, in the design and interpretation of clinical and preclinical experiments, and the acquisition and management of data. Core services will be critical for the clinical trials of the Projects, and their use of high-dimensional methodologies of gene expression profiling (GEP), next-generation sequencing (NGS) and Reverse Phase Protein Arrays (RPPAs). The Core will incorporate sound experimental design principles within each Project, specific to the scientific issues being addressed. Each Project will be provided with tailored analyses, accompanied by appropriate and sometimes novel biostatistical or bioinformatics methods. Core leaders will work with Project investigators to identify quantitative measures that can be used to test study hypotheses, including determining sample sizes to ensure sufficient power for the studies. The leaders of the Core will confer regularly with Project investigators to discuss the design and conduct of research projects, evaluate results of analyses, discuss potential new research initiatives and directions within the SPORE, and promote publication of findings. Interactions between the Core and Projects, as well as other integration, will be facilitated by a web-accessible database of relevant information generated by each Project, to be developed and maintained by the Core.
The main objectives of the Biostatistics and Bioinformatics Core are to: 1) Provide biostatistics and bioinformatics expertise in the design and conduct of laboratory experiments and clinical trials arising from the research proposed in this application; 2) Provide biostatistics and bioinformatics analysis and interpretation of all data collected under the SPORE Projects, Career Enhancement Program Projects, Developmental Projects, and other Cores; 3) Collaborate and assist all project investigators with the publication of scientific results; and 4) Develop and maintain a web-accessible, SPORE-specific database of relevant information for all Projects.
Developmental Research Program
Program Directors:
Russell Broaddus, MD, PhD (MD Anderson Cancer Center)
Daniel Carson, PhD (Rice University)
The purpose of the Developmental Research Program (DRP) is to fund promising projects by investigators whose current work may not focus exclusively on endometrial cancer, but who propose highly innovative translational studies of endometrial cancer that could become full SPORE projects or compete successfully for funding outside of the SPORE mechanism. The DRP provides a unique venue for making available significant financial support, and for demonstrating active institutional support, through a program that is rapidly responsive to new ideas or initiatives. Moreover, this program is rooted in a spirit of collaboration espoused by the SPORE investigators, who have an extensive track-record of bringing investigators from other disciplines into the field of endometrial cancer research. The strength of the Developmental Research Program rests in its ability to make available financial support and access all the critical expertise and resources within the entire SPORE, including SPORE Cores. This will allow us to develop important collaborative, multi-investigator, multi-institutional research projects with the support of innovative, investigator-initiated projects that have the potential to flourish into reliable and productive translational research projects for the SPORE. Pre-proposals in the form of 1-page letters of intent will be solicited by the Program, and applicants with pre-proposals that are highly competitive for the goals of this program will be invited to submit a full proposal for review. The DRP Directors will help investigators submitting proposals to formulate relevant translational research aims and plans, as many applicants may not have prior expertise in this type of research. This process will therefore be a major educational activity that is further anticipated to stimulate translational research in endometrial cancer and encourage the participation of both basic science researchers and clinical investigators in translational research.
Career Enhancement Program
Program Directors:
Diane Bodurka, MD
Karen H. Lu, MD
The goal of the Career Enhancement Program (CEP) is to develop highly trained, exceptional new investigators dedicated to translational research in the early detection, prevention, and treatment of endometrial cancer. These investigators and their research will ultimately help to reduce the morbidity and mortality from this disease. The CEP will 1) recruit and train physicians and basic scientists to enable them to become highly skilled translational investigators in the field of endometrial cancer; 2) provide specific knowledge of research in endometrial cancer that will enhance the ability of awardees to conduct innovative translational science that will directly impact the understanding and treatment of this disease; and 3) re-direct individuals who have already shown considerable scientific promise into endometrial cancer research. To achieve this goal, the SPORE CEP will provide at least two awards annually for up to two years, funded from the SPORE and/or matching funds or philanthropic funds from MD Anderson. We will aggressively recruit the most promising new investigators and institute an individualized development plan with clinical and laboratory mentors and a mentoring committee, coaching in grant and manuscript writing, leadership training, networking with endometrial cancer scholars, and completing and publishing a translational endometrial cancer manuscript in a peer-reviewed journal. The CEP will also encourage and support awardee presentations at national meetings.