The University of Texas MD Anderson Cancer Center SPORE in Ovarian Cancer
The University of Texas MD Anderson Cancer Center
- Principal Investigator(s) Contact Information
- Overview
- Project 1: Capitalizing on PARPness in Ovarian Carcinoma
- Project 2: Role of Macrophages in Resistance to Anti-VEGF Drugs in Ovarian Cancer
- Project 3: SIK2 Provides a Novel Target for Ovarian Cancer Therapy in Combination with Paclitaxel and Inhibitors of PARP
- Administrative Core
- Pathology Core
- Biostatistics and Bioinformatics Core
- Developmental Research Program
- Career Enhancement Program
Principal Investigator(s) Contact Information
Robert C. Bast, Jr., MD
University of Texas M.D. Anderson Cancer Center
Department of Experimental Therapeutics
1515 Holcombe Boulevard, Unit 355
Houston, TX 77030
Tel: (713) 792-7743
Fax: (713) 792-7864
Anil Sood, MD
Department of Gynecologic Oncology
CPB 6.3244, Unit 1362
U. T. M.D. Anderson Cancer Center
1155 Herman Pressler
Houston, TX 77030
Tel: (713) 745-5266
Fax: (713) 792-7586
Overview
The overall goal of the University of Texas MD Anderson Cancer Center SPORE in Ovarian Cancer is to improve outcomes for ovarian cancer patients by developing novel therapies that are based on the molecular, cellular and clinical biology of each patient's disease and that overcome intrinsic and acquired drug resistance. While the median survival of ovarian cancer patients has increased significantly over the past three decades, less than 30% of ovarian cancer patients survive long term. Poor outcomes relate to late diagnosis and to the persistence of dormant drug resistant cancer cells.
The three projects supported by this SPORE utilize novel targeted therapies and predictive biomarkers to improve outcomes for women with ovarian cancer, combining PARP inhibitors with novel agents that overcome adaptive drug resistance, guided by biomarkers that predict PARPi-sensitivity (Project 1); overcoming resistance to anti-angiogenic therapies by depleting tumor associated macrophages (Project 2); and targeting a kinase in cancer cells that regulates sensitivity to paclitaxel (Project 3). These projects challenge and seek to shift current paradigms in translational and clinical research in several ways. Project 1 will test the utility of a series of biomarkers designed to predict benefit from PARP inhibitors in trials with novel drug combinations with PARP inhibitors and seek additional rational drug combinations with PARP inhibitors that could be moved to clinical trials. Project 2 will test the role of a CSF-1 receptor inhibitor in improving the efficacy of bevacizumab therapy. In addition, potential biomarkers of response as well as additional drug combinations will be developed. If the proposed translational trial is positive, the use of selective CSF receptor inhibitors could be administered routinely to increase response to bevacizumab, changing clinical practice and improving outcomes. Project 3 will undertake a first-in-human trial of a novel inhibitor of salt-induced kinase (SIK2) that enhances sensitivity to paclitaxel, carboplatin and PARP inhibitors. This trial will translate an original observation by investigators at MD Anderson that SIK2 is required for centrosome splitting and can activate PI3K in ovarian cancer cell lines and xenografts.
Project 1: Capitalizing on PARPness in Ovarian Carcinoma
Project Co-Leaders:
Gordon B. Mills, MD, PhD
Shannon N. Westin, MD
Ovarian cancer incidence and mortality have remained essentially unchanged during the modern era of cancer treatment. Thus, there is a clear unmet need to improve on the current treatment paradigm, which yields upfront tumor shrinkage, but rarely durable remissions. High-grade serous ovarian cancer (HGSOC) is the most common subtype of ovarian cancer and is characterized by p53 mutations and defects in the homologous recombination (HR) DNA repair pathway. HR defects caused by germline and somatic BRCA1/2 aberrations, as well as aberrations in other pathway members, have been proposed to lead to synthetic lethality in combination with inhibition of poly (ADP-ribose) polymerase-1 (PARP). However, crucial gaps in knowledge exist that hinder our long-term goal of optimal implementation of PARP inhibitors (PARPi) into management of HGSOC including: 1) Identification and refinement of biomarkers of benefit from PARPi ("PARPness") and 2) development of rational PARPi combination therapies predicted to increase PARPi activity in HR-incompetent tumors, render HR-competent tumors responsive to PARPi or prevent/abrogate adaptive resistance to PARPi.
In a prior SPORE project, Drs. Mills and Westin developed DNA, RNA and protein PARPness assays to predict those patients who would benefit from PARPi treatment. They also characterized new members of the HR pathway, providing approaches to identify an expanded population of patients likely to benefit from therapy, despite wild type BRCA1/2. In this SPORE project, they will complete an ongoing multi-arm combination trial with PARPi and phosphatidylinositol 3-kinase inhibitors and implement a re-sensitization trial in PARPi resistant patients with Wee1 inhibition compared to PARPi plus Wee1i. These trials were founded on robust preliminary data from cell line, patient-derived xenograft (PDX) cancer models and animal models and will allow the investigators to refine the utility of biomarkers to predict response and resistance of HGSOC to PARPi.
PARPi have demonstrated modest clinical success as monotherapy. Work from the Mills laboratory and others suggests that the optimal benefit of PARPi will require identification of rational combination therapies that increase the activity of PARPi in HR-incompetent tumors and render HR-competent tumors responsive to PARPi. There is also a growing cohort of patients who have failed single agent PARPi therapy; therefore, methods to re-sensitize patients to PARPi are needed. To achieve these goals, the investigators will implement a systematic approach using preclinical models of novel cell lines and PDX to identify mechanisms to bypass intrinsic, adaptive, and acquired resistance.
Aim 1. To identify and refine biomarkers of benefit from PARPi in ovarian cancer.
Aim 2. To establish a preclinical framework to identify and prioritize rational combination therapies in ovarian cancer.
Project 2: Role of Macrophages in Resistance to Anti-VEGF Drugs in Ovarian Cancer
Project Co-Leaders:
Anil Sood, MD
Robert L. Coleman, MD
The progressive growth of most solid tumors and their metastases is dependent on the formation of a new blood supply, i.e., angiogenesis. Vascular endothelial growth factor (VEGF) is a primary mediator of the pathologic angiogenesis that accompanies tumor growth and has emerged a key target for therapeutic intervention. Unfortunately, however, the clinical use of anti-VEGF therapies has produced only modest benefits in progression-free or overall survival, most likely due to adaptive changes that take place in the tumor microenvironment. Results generated from Dr. Sood's laboratory indicate that macrophages may contribute to the development of resistance to anti-VEGF therapy in ovarian cancer. Macrophages are actively recruited into tumors by chemotactic agents, such as VEGF and macrophage colony-stimulating factor 1 (CSF-1), which are synthesized and secreted by cancer cells and stromal cells. The low oxygen concentrations and increased levels of lactate in the tumor microenvironment trigger macrophages to release vasoactive substances (e.g., prostaglandins, VEGF) that enhance tumor vascular permeability. Activated macrophages also produce VEGF and fibroblast growth factor that contribute to the pool of available endothelial cell mitogens.
Macrophage infiltration is associated with poor clinical outcome in patients with ovarian cancer. The investigators noted that robust recruitment of macrophages and bone marrow-derived suppressor cells coincides with acquisition of resistance to anti-VEGF treatment in preclinical models of ovarian cancer. Moreover, they determined that targeted depletion of macrophages with an anti-CSF-1 receptor inhibitor significantly improved the efficacy of anti-VEGF therapy in experimental tumors. However, the mechanisms by which this occurs are not well understood. In this project, they will explore the mechanisms by which macrophages contribute to adaptive resistance to anti-VEGF treatment, and identify the underlying signaling pathways. They will also test the efficacy of combined targeting of VEGF and macrophages in vivo and in ovarian patients.
Aim 1. To identify the biologic roles of macrophages in adaptive resistance to anti-VEGF drugs.
Aim 2. To determine the in vivo efficacy of targeting tumor-associated macrophages in combination with anti-VEGF treatment.
Aim 3. To evaluate the ability of emactuzumab (CSF-1 receptor inhibitor) to overcome microenvironment adaptive changes mediated by tumor-associated macrophages in patients not progressing on bevacizumab.
Project 3: SIK2 Provides a Novel Target for Ovarian Cancer Therapy in Combination with Paclitaxel and Inhibitors of PARP
Project Co-Leaders:
Robert C. Bast, Jr., MD
Amir Jazaeri, MD
Over the last three decades, 5-year survival has improved for patients with epithelial ovarian cancer, but long-term survival has not changed. An enhanced response to paclitaxel (or carboplatin) in a larger fraction of patients could improve outcomes. Dr. Bast's laboratory used high-content siRNA-based kinome screens to identify candidate modulators of mitotic progression that may influence clinical paclitaxel response. The most promising target to date is the serine-threonine kinase salt-induced kinase 2 (SIK2). Indeed, these investigators have found that knocking down SIK2 induces polyploidy, inhibits ovarian cancer growth and enhances paclitaxel and cisplatin sensitivity in cell lines and experimental ovarian tumors. SIK2 is required for normal centrosome splitting and also phosphorylates p85a, driving activation of PI3K, as well as HDAC5, modifying chromatin. The kinase is overexpressed in 30% of ovarian cancers where it is associated with paclitaxel resistance and decreased progression-free survival. Preliminary data suggest that there is marked synergy between a small molecule SIK2 inhibitor, paclitaxel and PARP inhibitors. In this SPORE project, Drs. Jazaeri and Bast will perform the first clinical evaluation of a selective SIK2 inhibitor.
Aim 1. To perform a phase I trial of the SIK inhibitor ARN-3261 alone (Phase IA) and in combination with weekly paclitaxel (Phase IB) followed by a randomized phase II trial of weekly paclitaxel +/- ARN-3261.
Aim 2. To determine the optimal sequence of administration of SIK2 inhibitors and cytotoxic drugs in cell culture and in experimental models of ovarian cancer.
Aim 3. To identify targets that produce synthetic lethality in ovarian cancer cells treated with SIK2 inhibitors.
Administrative Core
Core Director:
Robert C. Bast, Jr., MD
The primary function of the Administrative Core is to direct the overall scientific quality of the SPORE and ensure communication, cooperation, and integration between all projects and cores. Dr. Bast will interface with all project leaders and core directors and will actively oversee all research activities. He is also responsible for facilitating communications and research progress and directing all meetings of SPORE investigators. Dr. Sood is also involved in overall decision making and is responsible for overseeing the SPORE Career Enhancement Program (CEP) and Developmental Research Program (DRP). Dr. Karen Lu will direct the data management for the SPORE through REDcap and supervise the development of an EPIC-based longitudinal disease registry. Drs. Lu, Sood and Bast will work together to mentor CEP awardees.
The Administrative Core will have overall fiscal and scientific responsibility for all projects and cores, including the employment of key personnel to ensure the efficient and effective financial management of large, complex clinical trials and laboratory research projects. Fiscal and budgetary functions begin with the set-up of all new post-award accounts and subcontracts. The core will monitor the overall compliance of the SPORE in conjunction with all general governmental and specific NCI regulations and requirements. Core personnel communicate with and confer with the NCI project director and other staff to ensure all necessary reporting requirements are met, including compliance with the PMCID policy. The Administrative Core organizes all meetings of the SPORE Internal and External Advisory Board Committees and coordinates with other organ-site SPORES and ovarian cancer SPORES to promote and maintain communication and integration. Core personnel produce annual RFAs for the CEP and DRP awards and distribute those announcements to faculty at MD Anderson Cancer Center and other institutions within the Texas Medical Center.
Pathology Core
Core Directors:
Russel Broaduss, MD, PhD
Jinsong Liu, MD, PhD
The unique requirements and scope of this SPORE proposal necessitate dedicated personnel and services beyond those presently supported by the MD Anderson Cancer Center Pathology Centralized Tissue Repository or the Gynecological Oncology Tumor Bank. The quality control and quality assurance activities needed for high-quality research, including collaboration with other SPOREs and investigators outside MD Anderson Cancer Center, require additional personnel and effort commitment that are beyond the scope of the existing resources. The Ovarian Cancer SPORE Pathology Core expands and complements the services provided by the existing Gynecological Oncology Tumor Bank, without duplication. The SPORE Pathology Core does not require additional laboratory space or major equipment as these essential resources are already provided for by the Gynecological Oncology Tumor Bank and Centralized Tissue Repository.
The SPORE Pathology Core is under the direction of Drs. Russell Broadus and Jinsong Liu. Both investigators are experienced gynecologic pathologists with established NCI-funded research laboratories at MD Anderson Cancer Center. Dr. Broadus is responsible for quality assurance and reviews all frozen slides from diseased tissues to confirm the diagnosis and determine the percent viability of the tumor tissues. The core also performs testing on tissue sections to confirm that the specimen has high quality, intact RNA. Dr. Broaddus supervises any microdissection of slides, while Dr. Liu selects appropriate cases to be incorporated into ovarian cancer tissue microarrays. Both co-directors have extensive experience in the histopathological examination of experimental tumor models and Dr. Liu has considerable expertise in establishing PDX models. The overall goal of the Pathology Core is to provide frozen tissue, paraffin-embedded tissue, and histopathologic expertise related to the specific needs of the research projects comprising this SPORE proposal. To meet this goal, the core has established the following Specific Aims:
Aim 1. To maintain a frozen and paraffin-embedded tissue repository of ovarian cancers, benign ovarian processes, and normal ovary.
Aim 2. To provide pathological review for all clinical specimens utilized in the SPORE projects and to provide histopathological technical services to all SPORE investigators as needed.
Aim 3. To establish a blood/urine/ascites fluid collection from patients undergoing surgery for ovarian cancer and benign ovarian disease.
Aim 4. To create and maintain a relational SPORE database for all samples collected by the SPORE Pathology Core.
Biostatistics and Bioinformatics Core
Core Directors:
Ying Yuan, PhD
Jing Ning, PhD
All projects in the Ovarian SPORE generate large amounts of data using a wide variety of assays, and are associated with clinical trials testing the efficacy of new therapeutic options. The Biostatistics and Bioinformatics Core provides the quantitative expertise required to distill useful information from these various types of data, and to design and analyze the data from the clinical trials. Indeed, members of Core 2 have assisted with the designs of all trials proposed in the SPORE, and have participated in weekly meetings with the SPORE PIs for several years to (a) identify and define relevant clinical questions, (b) discuss the types of data required to answer these questions, and (c) assist with obtaining and processing these data to reach associated conclusions.
The Biostatistics and Bioinformatics Core is under the leadership of Dr. Keith Baggerly. Dr. Baggerly's own research interests are in "forensic bioinformatics" where aspects of raw data and reported results are used to infer what methods must have been employed. However, the primary purpose of the Biostatistics and Bioinformatics Core is not to pursue its own research, but rather to provide analytical support adequate to advance the research pursued in the projects. The core will achieve this objective by completing the following specific aims:
Aim 1. Provide statistics and data analyses required for the projects and cores to achieve their specific aims.
Aim 2. Provide bioinformatics expertise required for analyses and interpretation of high-throughput assay data.
Aim 3. Assist with design and implementation of new trials and studies arising from SPORE research.
Developmental Research Program
This program provides seed funds to support innovative, high-impact, translational cancer research projects.
Career Enhancement Program
This program provides seed funding to nurture investigators interested in translational cancer research.