University of Pittsburgh HCC Ovarian Cancer SPORE

University of Pittsburgh

Principal Investigators

Overview

The overall goal of the UPMC Hillman Cancer Center (HCC) OvCa Specialized Programs of Research Excellence (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 the ovarian cancer (OvCa) stromal progenitor's 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 response to immune checkpoint inhibitor therapy in patients with OvCa.

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 provide research funding to investigators from under-represented minority groups in a cost-sharing and proactive manner. They will provide a pipeline of potential future SPORE Projects. All SPORE, CEP, and DRP projects will 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 patients with OvCa seen at HCC 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: TEZH2 Inhibition to Prevent/Overcome Chemoresistance Siglec15 as a New Target for Lung Cancer Immunotherapy

Project Co-Leaders

• Lan Coffman, M.D. (Basic Co-leader)
• Robert Edwards, M.D. (Clinical Co-leader)

Overcoming chemotherapy resistance and maintaining sensitivity to platinum, the most effective chemotherapy in ovarian cancer, 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. However, no strategies yet 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 that is necessary for CA-MSC formation. Importantly, the CA-MSC phenotype appears to be reversible. CA-MSC reversion or ‘normalization’ correlates with improved sensitivity to platinum and patient survival. Our preliminary data indicate that pharmacologic inhibition of EZH2 blocks the reprogramming of MSC into CA-MSC. This 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: Mechanism-based approaches to counter TKI resistance in EGFR mutant lung cancer

Project Co-Leaders

• Rugang Zhang, Ph.D. (Translational Co-leader)
• Haider Mahdi, M.D. (Basic Co-leader)

Our central hypothesis is that targeting BRD4 activity using a clinically applicable BET inhibitor is sufficient to overcome resistance to PARPi that has developed in recurrent OvCa. We also hypothesize that targeting BRD4 will sensitize the tumor to PARPi by simultaneously downregulating HR activity, specifically BRCA1, RAD51 and TOPBP1 expression, and by 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 using samples 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 that has limited treatment options.

Project 3: Hedgehog Inhibition to Enhance Response to ICI Therapy

Project Co-Leaders

• Anda Vlad, M.D., Ph.D. (Basic Co-leader)
• Ronald Buckanovich, M.D., Ph.D. (Clinical Co-leader)
• Sarah Taylor, M.D., Ph.D. (Clinical Co-leader)

When it is effective, immune checkpoint inhibitor (ICI) therapy can significantly improve the outcome of patients with ovarian cancer (OvCa). However, only 10-20% of patients with OvCa 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 creates 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 Co-Directors

• Ronald Buckanovich, M.D., Ph.D.
• Robert Edwards, M.D.

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. 

Biostatistics and Bioinformatics Core

Core Co-Directors

• Curtis Tatsuoka, Ph.D.
• Riyue Bao, Ph.D.

The Biostatistics and 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 data are analyzed in the appropriate scientific context. This increases 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.

Translational Pathology Core

Core Co-Directors

• Francesmary Modugno, Ph.D.
• Esther Elishaev, M.D.

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 Pennsylvania 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. It ultimately will improve the lives of patients suffering from this devastating disease.

Developmental Research Program

Program Co-Directors

• Alexander Olawaiye, M.D.
• Katherine Aird, Ph.D.

The University of Pittsburgh HCC Ovarian Cancer SPORE Developmental Research Program (DRP) supports early-phase projects. These projects have the potential to open new areas of translational research and lead to reduced morbidity and mortality in patients with ovarian cancer. The overall mission of the DRP is to stimulate research in ovarian cancer that will lead to greater understanding of ovarian cancer biology, better treatment, and improved outcomes for patients with 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 ovarian 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 are 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.

Career Enhancement Program

Program Co-Directors

• Francesmary Modugno, Ph.D.
• Katherine Aird, Ph.D.

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. It also includes 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
• Aim 3: 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.