HCC Ovarian Cancer SPORE
University of Pittsburgh
Principal Investigator(s):
Ronald Buckanovich, MD, PhD
Robert Edwards, MD
- Principal Investigator(s) Contact Information
- Overview
- Project 1: Title: EZH2 Inhibition to Prevent/Overcome Chemoresistance
- Project 2 : Combination PARPi-BETi to Overcome PARPi Resistance
- Project 3: Hedgehog Inhibition to Enhance Response to ICI TherapyH
- Administrative Core
- Translational Pathology Core
- Biostatistics and Bioinformatics Core
- DRP: Developmental Research Program
- CEP: Career Enhancement Program
Principal Investigator(s) Contact Information
Ronald Buckanovich, MD,PhD
Professor of Medicine
Director of the Ovarian Cancer Center of Excellence
Co-Director of the Womens Cancer Research Center
Magee-Womens Research Institute
UPMC Hillman Cancer Center
University of Pittsburgh204 Craft Avenue, B333
Pittsburgh, PA 15213
412-641-4721
Robert Edwards, MD
Milton Lawrence McCall Professor and Chair
Department of Obstetrics, Gynecology & Reproductive Sciences
Co-Director, Gynecologic Oncology Research
Magee-Womens Hospital of UPMC
300 Halket Street
Pittsburgh, PA 15213
412-641-4212
Overview
The overall goal of the UPMC Hillman Cancer Center (HCC) OvCa SPORE is to prevent and/or overcome therapeutic resistance to improve patient survival. Each of the SPORE’s three Projects evolved from the innovative concepts and findings of SPORE investigators. Each project involves a clinical trial with a new agent. In addition, each project, through complementary investigator expertise, incorporates critical translational aims to identify patients most likely to respond to therapy.
Project 1 will assess the ability of inhibitors of the epigenetic regulator EZH2 to prevent/overcome OvCa stromal progenitor cell-driven resistance to platinum-based chemotherapy.
Project 2 will determine whether BET inhibitors, which downregulate critical DNA repair and cell cycle checkpoint proteins, can reverse resistance to PARP inhibitors.
Project 3 will test whether inhibitors of the hedgehog signaling pathway, which drives tumor immune exclusion, can improve OvCa patient response to immune checkpoint inhibitor therapy.
The HCC OvCa SPORE will include a Career Enhancement Program (CEP) and Developmental Research Program (DRP) in order to both encourage early career investigators to enter the field of translational OvCa research and engage more established investigators in OvCa research. The CEP and the DRP, which are cost-shared and proactive at providing research funding to investigators from under-represented minority groups, will provide a pipeline of potential future SPORE Projects. All SPORE, CEP, and DRP Projects will be receive fiscal and scientific oversight from an Administrative Core and support from two shared resource cores. The Translational Pathology Core will collect, annotate, archive, and distribute biospecimens and clinical data derived from the more than 300 HCC OvCa patients seen each year. It will also develop new preclinical experimental models that behave more like human OvCa. The Biostatistics and Bioinformatics Core will aid in design and analysis of all studies, including ‘omic’ technologies that can provide molecular and spatial characterization of individual cells within a tumor.
Project 1: Title: EZH2 Inhibition to Prevent/Overcome Chemoresistance
Project Co-Leaders:
Lan Coffman, MD (Basic)
Robert Edwards, MD (Clinical)
The ability to overcome the development of chemotherapy resistance and maintain sensitivity to the most effective chemotherapy in ovarian cancer, platinum, is critical to improving outcomes in ovarian cancer. The ovarian cancer tumor microenvironment (TME) is an important, though understudied, mediator of treatment resistance. Specifically, the stromal composition of this TME dramatically influences how cancer responds to chemotherapy, yet no strategies exist to target the cancer-supportive properties of the stromal TME. Carcinoma-associated mesenchymal stem/stromal cells (CA-MSCs) are stromal progenitor cells that dictate the composition and function of the stromal TME. CA-MSCs strongly promote the development of chemotherapy resistance through the secretion of growth factors such as BMP2 and BMP4 and alteration of the extracellular matrix (ECM). CA-MSCs arise from cancer mediated epigenetic reprogramming of normal MSCs through altered genomic localization of the histone methyltransferase EZH2. WT1, a transcription factor highly upregulated in CA-MSCs, appears to drive this altered genomic localization of EZH2 necessary for CA-MSC formation. Importantly, the CA-MSC phenotype appears to be reversible and CA-MSC reversion or ‘normalization’ correlates with improved sensitivity to platinum and patient survival. Our preliminary data indicate pharmacologic inhibition of EZH2 blocks the reprograming of MSC into CA-MSC and increases CA-MSC normalization to prevent chemotherapy resistance. We thus hypothesize that inhibiting EZH2 will disrupt stromal support of ovarian cancer leading to improved treatment response, reduction in metastasis, and delayed disease recurrence with maintenance of platinum sensitivity.
Specific Aims
Aim 1: Conduct a phase 1 dose-escalation study of the second generation EZH2 inhibitor, CPI-0209, in combination with Carboplatin in platinum sensitive, recurrent ovarian cancer.
Aim 2: Determine the impact of EZH2 inhibition on the ovarian stromal TME.
Aim 3: Determine the role of WT1 in mediating EZH2-driven CA-MSC reprogramming and chemotherapy resistance.
Project 2 : Combination PARPi-BETi to Overcome PARPi Resistance
Project Co-Leaders:
Rugang Zhang, PhD (Basic)
Haider Mahdi, MD (Clinical)
Our central hypothesis is that targeting BRD4 activity using clinically applicable BET inhibitor is sufficient to overcome resistance to PARPi developed in recurrent OvCa. We also hypothesize that targeting BRD4 will sensitize tumor to PARPi by simultaneously downregulating HR activity, specifically BRCA1, RAD51 and TOPBP1 expression, and impairing the G2/M phase of the cell cycle by suppressing WEE1 activity, leading to DNA damage accumulation and mitotic catastrophe. Accordingly, the objective of the present study is to evaluate the safety and efficacy of a combination of PARPi and BETi in recurrent PARPi-resistant platinum-sensitive OvCa. We also plan to assess the impact of PARPi-BETi combination on functional HR activity and percent reduction compared to baseline and correlate with objective response to therapy. Further, we plan to investigate the mechanistic basis of these findings in patient-derived models obtained from the patients enrolled in the trial.
Specific Aims
Aim 1: Determine the safety and efficacy of PARPi combined with BETi in patients with recurrent PARPi-resistant OvCa in a phase Ib clinical trial.
Aim 2: Investigate the impact of the combined regimen on modulating HR and DNA damage response (DDR) pathways as well as G2-M cell cycle checkpoint using tissue and circulating tumor DNA samples both at baseline, on treatment and at time of progression.
Aim 3: Investigate the mechanisms of response and resistance to the combination regimen in preclinical models. The potential impact is significant as there is an urgent need to overcome resistance to PARPi in OvCa.
This project investigates a novel new therapeutic direction combining PARPi with epigenetic therapy by BETi. PARPi resistance is a major challenge given that PARPi are now approved in first line and recurrent settings. Further, this study will investigate predictive biomarkers, which will help identify patients who benefit from this regimen. Successful execution of this study will provide a rationale to advance this regimen into scientifically rationalized trials focused on improving the outcome of this most lethal cancer with limited treatment options.
Project 3: Hedgehog Inhibition to Enhance Response to ICI TherapyH
Project Co-Leaders:
Anda Vlad, MD, PhD (Basic)
Ronald Buckanovich, MD, PhD (Clinical)
Sarah Taylor, MD, PhD (Clinical)
When effective, immune checkpoint inhibitor (ICI) therapy can significantly improve the outcome of patients with ovarian cancer (OvCa). However, only 10-20% of OvCa patients respond to ICI therapy. One reason for the low ICI response rate of OvCa may be OvCa’s unique immunosuppressive tumor microenvironment (TME), which is typified by a dense stroma infiltrated by immunosuppressive ‘M2’ tumor associated macrophages (TAMs). We recently found that ovarian carcinoma-associated mesenchymal stem cells (CA-MSC) orchestrate an immunosuppressive OvCa TME; differentiating into BIGH3 expressing fibroblast/tumor stroma, recruiting monocytes to the stroma, and promoting the differentiation of immunosuppressive BIGH3 expressing ‘M2’ TAMs. The combined effect is that CA-MSC drive tumor immune exclusion and a resultant resistance to ICI therapy. Importantly, we find that hedgehog inhibitors (HHi) reverse CA-MSC-driven immune exclusion, promote M2 to M1 TAM conversion, and restore response to ICI therapy. HHi therapy down-regulates BIGH3 in CA-MSC and TAMs, and promotes the conversion of TAMs from an M2 to and M1 phenotype. Our studies are consistent with numerous recent reports that HHi promote M1 macrophage polarization and promote anti-tumor immunity. Based on these results, we hypothesize that CA-MSC create an immunosuppressive OvCa TME and that HHi will reverse CA-MSC mediated immune-suppression and enhance patient response to ICI therapy.
Specific Aims
Aim 1: Conduct a single arm Phase-II clinical trial evaluating Atezolizumab (aPD-L1) combined with Vismodegib (HHi) in patients with platinum resistant recurrent ovarian cancer. Primary endpoints will be efficacy and safety. Secondary endpoints will be duration of response, PFS, OS and translational correlatives.
Aim 2: Evaluate the impact of HHi on patients’ tumor immune infiltrates and peripheral chemokines and determine if changes predict response to therapy.
Aim 3: To assess BIGH3 as a driver of tumor immune exclusion and immunotherapeutic target. Using murine models of OvCa, we will assess the impact of BIGH3 on immune effector migration and function and determine if anti-BIGH3 therapy can enhance ICI response in murine tumor models.
Administrative Core
Core Directors:
Ronald Buckanovich, MD, PhD
Sarah Taylor, MD, PhD
The HCC OvCa SPORE Administrative Core (Core A) is co-directed by SPORE PIs Ronald Buckanovich, MD, PhD and Robert Edwards, MD. Core A will:
Specific Aims
Aim 1: Provide scientific, fiscal, and general administrative oversight to all SPORE components.
Aim 2: Work to facilitate the research productivity of the three SPORE Projects.
Aim 3: Expand the utility and efficiency of the SPORE’s two Shared Resource Cores.
Aim 4: Ensure the success of the Career Enhancement Program (CEP) and Developmental Research Program (DRP) to generate a pipeline of new OvCa investigators and projects.
Core A will coordinate sharing of SPORE data as well as internal and external communications and budgets. Core A will convene monthly meetings attended by all SPORE Investigators, coordinate periodic administrative and scientific reviews, release and publicize RFAs and arrange for the review of received CEP and DRP applications, and work closely with the NCI Translational Research Program Office. It will provide the administrative framework through which the SPORE Executive Committee, Internal Advisory Board (IAB), and External Advisory Board (EAB) can evaluate program activities and will redirect resources, as appropriate, to maximize progress toward the SPORE’s translational goals.
Translational Pathology Core
Core Directors:
Francesmary Modugno, PhD
Esther Elishaev, MD
The Hillman Cancer Center (HCC) Ovarian Cancer (OvCa) SPORE Translational Pathology Core (TPC) will provide four key services to facilitate innovative translational studies.
Specific Aims
Aim 1: Procuring quality-controlled, pathology-reviewed, and clinically-annotated biospecimens,
Aim 2: Extracting, processing, and storing de-identified clinical data that can be easily integrated with other data types (e.g., genotype, omics, metadata).
Aim 3: Securely sharing biospecimens and data.
Aim 4: Developing patient-derived tumor models for therapeutic and mechanistic studies. The TPC provides these critical services to HCC OvCa SPORE investigators, other NCI-funded OvCa SPOREs, and the greater OvCa research community.
The biorepository enables all persons seen at HCC gynecologic cancer clinics in southwestern PA to donate samples. A novel aspect of the TPC is using primary patient tissues to generate preclinical models to facilitate basic science and preclinical studies. Primary tumor is also used to generate patient-derived tumor xenografts (PDX). The TPC draws on resources already available through HCC, including the Cancer Center Support Grant (CCSG) cores and the Magee-Womens Research Institute and Foundation (MWRI). As such it efficiently and effectively provides and facilitates the testing of clinically derived data and biospecimens to support OvCa SPORE investigators, and the greater ovarian cancer research community, ultimately improving the lives of patients suffering from this devastating disease.
Biostatistics and Bioinformatics Core
Core Directors:
Curtis Tatsuoka, PhD
Riyue Bao, PhD
The Biostatistics/Bioinformatics Core of the Hillman Cancer Center (HCC) Ovarian Cancer (OvCa) SPORE provides services for the design of experiments and the analysis of in vitro, in vivo, clinical, translational and -omics data. The investigators and staff of both segments of the Core have significant experience in research in ovarian cancers, so that data are analyzed in the appropriate scientific context, increasing the Core’s efficiency and effectiveness compared to general purpose data analysis services. Biostatistics and Bioinformatics combines classic statistical techniques with contemporary Bayesian, machine learning and genomics methods to ensure that every research project, Developmental Research Program and Career Development Program awardee in the SPORE has access to the most appropriate analyses. The Core will also work closely with the Administrative Core and the Translational Pathology Core to ensure that data flows between laboratories, clinics and analysts are efficient, and that data and resource sharing can be effective and comprehensive.
Specific Aims
Aim 1: To collaborate with the UW Prostate Cancer SPORE investigators in study design, analysis, and interpretation of data, and writing of scientific manuscripts.
Aim 2: To ensure the transparency and validity of statistical and bioinformatic analysis via rigorous data collection, standardization of the variety of data that arise from the UW Prostate Cancer SPORE projects, confidential and secure data archiving and data sharing, and centralized data management activities including validation and consistency checking of all collected data.
Aim 3: To develop new statistical and bioinformatics methods relevant to the individual projects.
DRP: Developmental Research Program
Program Directors:
Alexander Olawaiye, MD
Katherine Aird, PhD
The University of Pittsburgh HCC Ovarian Cancer SPORE Developmental Research Program (DRP) supports early phase projects that have the potential to open new areas of translational research, and lead to reduced morbidity and mortality in patients with prostate cancer. The overall mission of the DRP is to stimulate research in prostate cancer that will lead to greater understanding of prostate cancer biology, better treatment, and improved outcomes for this disease. Developmental projects include research focused on basic science discoveries, prevention, early detection, treatment, development of prognostic and predictive biomarkers, as well as survivorship.
Specific Aims
Aim 1: Stimulate creation of multi-disciplinary teams to conduct impactful research studies in prostate cancer that include basic, clinical, and population researchers, as well as collaboration with outside SPORE institutions and investigators.
Aim 2: Provide 1-2 years of funding to support investigator-initiated research that may lead to subsequent grants, clinical trials, or insight on project feasibility, as well as become a future SPORE project.
Aim 3: Support high-risk, high-reward ideas that may be too early for traditional grant mechanisms but deemed innovative and important to explore.
Aim 4: Monitor progress of funded DRP projects and recommend which projects should be advanced to a full SPORE project.
CEP: Career Enhancement Program
Program Directors:
Francesmary Modugno, PhD
Katherine Aird, PhD
The mission of the Hillman Cancer Center (HCC) Ovarian Cancer (OvCa) SPORE Career Enhancement Program (CEP) is to foster the development of independent translational ovarian cancer researchers who will impact ovarian cancer care. This includes supporting not only outstanding early career scientists, but also experienced investigators wishing to transition their careers into translational ovarian cancer research, or clinical investigators well versed in the design and performance of clinical trials who wish to broaden their translational research experience. The HCC OvCa SPORE is fully committed to diversity and has established collaborations with external institutions to increase the participation of under-represented scientists in the CEP. The CEP will directly facilitate career development through:
Specific Aims
Aim 1: Constructive proposal review and feedback;
Aim 2: research training with a mentor chosen from among diverse faculty with broad expertise and experience in academic career development; and iii) access to development programs, including monthly ovarian cancer research group meetings, monthly SPORE meetings, the annual HCC and Magee Womens Research Institute retreats, and the annual SPORE retreat.
Projects that show the greatest likelihood of impact and translation to the clinic can evolve into future full SPORE projects. Ultimately, the CEP provides a vital mechanism for achieving the SPORE’s goal of developing the next generation of ovarian cancer researchers committed to overcoming this deadly disease.