Johns Hopkins University/University of Pennsylvania SPORE of Ovarian Cancer

Johns Hopkins University

Principal Investigator

University of Pennsylvania

Co-Principal Investigator

Overview

Ovarian cancer is one of the most aggressive cancers in women in the United States. It is often detected in its advanced stage, making it difficult to treat and a major cause of cancer morbidity and mortality. This team will evaluate innovative approaches for early diagnosis through the development of more effective diagnostic tools. They will investigate novel therapies that will minimize chemotherapy resistance and reduce recurrence after regular treatment. Clinical trials will support this research, and they are currently accepting eligible applicants.

This translational program is composed of three hypothesis-driven research projects, three shared core resources, the Career Enhancement Program, and the Developmental Research Program. Researchers from this program at both Johns Hopkins University and the University of Pennsylvania work closely to align and join their efforts in all three research projects of this SPORE.

Project 1: Diagnosis of ovarian cancer precursors and incipient carcinoma

Project Co-Leaders

• le-Ming Shih, M.D., Ph.D. (Basic Co-leader)
• Nickolas Papadopoulos, Ph.D. (Basic Co-leader)
• Ronny Drapkin, M.D., Ph.D. (Clinical Co-leader)

The current strategy for identifying HGSC precursors in the fallopian tube relies on morphological assessment of the fimbria, which is limited as it examines only a small fraction of the tubal epithelium, potentially missing critical lesions. We propose that brushing epithelium from surgically removed fallopian tubes and assessing aneuploidy and DNA methylation will provide more comprehensive sampling than routine pathology.

A key question is whether all serous tubal intraepithelial carcinoma (STIC) lesions are equivalent, or if some can regress, akin to early cervical neoplasms. Our studies will use novel models to investigate if certain amplified genes (e.g., CCNE1, RSF-1, MYC) drive more aggressive tumor biology and can serve as biomarkers for tumors that might benefit from alternative therapies explored in other SPORE projects. 

Project 2: Targeting CCNE1 overexpression in high grade serous ovarian cancer

Project Co-Leaders

• Fiona Simpkins (Clinical Co-leader)
• Erick Brown (Basic Co-leader)

High-grade serous carcinomas (HGSCs) exhibit significant molecular heterogeneity, with CCNE1 amplification being common and linked to platinum resistance and poor survival. The PIs of this SPORE have shown that CCNE1 amplification is an early event in HGSC precursors. Thus, CCNE1-amplified HGSCs pose a major clinical challenge. This proposal aims to develop treatment strategies for this patient subset.

ZN-c3, a next-generation WEE1 kinase inhibitor, has shown less heme toxicity in phase I trials than its predecessor, adavosertib. It is now progressing to a phase II clinical trial for HGSC, led by Dr. Simpkins. Our hypothesis is that WEE1 inhibitors (WEE1i) will be effective against CCNE1-overexpressing HGSCs and that additional molecular alterations will enhance responsiveness. We will evaluate CCNE1 as a biomarker for WEE1i response using clinical trial samples, assessing whether CCNE1 gene copy number or protein levels are more reliable predictors.

Additionally, we will explore if circulating tumor DNA (ctDNA) can be used to measure tumor CCNE1 copy number and identify sensitivity biomarkers using whole genome cfDNA analysis (DELFI), whole exome analysis, and RNA sequencing. Although WEE1i monotherapy is expected to be effective, we hypothesize that resistance to the drug will emerge. We further hypothesize that combining WEE1i with ATR inhibitors (ATRi) will overcome this resistance in CCNE1-amplified HGSCs. We will test the WEE1i-ATRi combination using annotated PDX and organoid models.

Furthermore, we expect DNA repair factors will be recruited to replication forks following WEE1i and ATRi treatment and that this will impact drug responsiveness and serve as potential biomarkers. These factors will be identified using iPOND2-QMS in CCNE1-amplified WEE1i-resistant cells. These studies aim to uncover mechanisms of drug resistance and identify high-priority biomarkers for future clinical trials.

Project 3: Identifying and targeting mediators of CNS metastasis from lung cancer

Project Co-Leaders

• Stephanie Gaillard, M.D., Ph.D. (Basic Co-leader)
• Tian-Li Wang, Ph.D. (Basic Co-leader)
• Philipp Oberdoerffer (Clinical Co-leader)

While less common than high-grade serous carcinoma, advanced ovarian clear cell and endometrioid carcinomas have the poorest 5-year survival rates for advanced-stage disease among all subtypes. Chemotherapy response rates for these patients are below 10%, and approximately 1% in recurrent cases, highlighting a dire unmet medical need.

ARID1A mutations are common in ovarian clear cell carcinoma and are linked to chemotherapy resistance. Our recent studies show that these mutations impair DNA double-strand break repair. Although ARID1A mutant ovarian clear cell carcinomas are not typically sensitive to PARP inhibitors (PARPi), we identified that alkylating agents like temozolomide (TMZ) exhibit synergistic anti-tumor activity with PARPi. TMZ-induced methylated DNA lesions are repaired by DNA base excision repair (BER), and our data indicate that ARID1A-deficient cells struggle to resolve these lesions, leading to enhanced replication fork stalling and collapse when combined with PARPi.

We hypothesize that in ARID1A mutant cells, TMZ-induced methylated DNA lesions and single-stranded DNA breaks increase reliance on PARP1. We will test this using isogenic ARID1A mutant and knockout cells, examining replication perturbations from TMZ/PARPi treatment. Additionally, we will investigate if BER inhibitors sensitize ARID1A wild-type tumors to PARPi combined with TMZ.

Finally, we will evaluate the clinical efficacy of the TMZ and PARPi (senaparib) combination in a phase II trial for ARID1A mutant ovarian clear cell and endometrioid carcinomas. This will be the first study to focus on this combination in tumors with ARID1A mutations.

Administrative Core

Core Co-Directors

• le-Ming Shih, M.D., Ph.D.
• Stephanie Gaillard, M.D., Ph.D.
• Ronny Drapkin, M.D., Ph.D.

The Administrative Core supports operations and communications, emphasizing key areas of coordination and oversight to enhance Core functionality. The Core leadership team is responsible for planning, managing, and directing the overall program. This ensures the achievement of strategic objectives and providing quality administrative support to all research projects, program (CEP and DRP), and other Cores. The team promotes resource sharing, fosters new research opportunities, and advocates for patients. They coordinate essential program interactions, including planning and evaluations, arranging and publicizing SPORE activities, monitoring data and safety, organizing advisory committee meetings, summarizing annual reports, and analyzing budgetary matters.

Computational and Biostatistical Core

Core Co-Directors

• Peng Huang, Ph.D.
• Leslie Cope, Ph.D.

The Computational and Biostatistics Core will provide comprehensive biostatistics and bioinformatics consultation and collaboration to all projects within this Ovarian SPORE. The Core will enhance the reproducibility of all clinical and laboratory studies through scientific rigor and transparency. Centralizing biostatistics and bioinformatics support within this Core ensures that the necessary expertise will be available to all projects, developmental studies, and faculty receiving career development awards. This Core provides each project with the resources needed to address its aims efficiently by sharing expertise across projects. It contributes to the dissemination of state-of-the-art quantitative techniques to all SPORE investigators. In addition, centralizing this resource, and tightly integrating biostatistics and bioinformatics support within it, will put Core members in an ideal position to initiate and promote interdisciplinary interactions among projects, thereby contributing to the bi-directional exchange.

Biorepository and Pathology Core

Core Co-Directors

• Amanda Fader, M.D.
• Tian-Li Wang, Ph.D.
• Ronny Drapkin, M.D., Ph.D.

The Biorepository/Pathology Core provides project-driven human bio-specimen service and pathology consultation to all investigators participating in this SPORE and to external collaborators. The availability of well-characterized, high-quality human tissues and biological fluids is pivotal to the translational projects within this SPORE. Furthermore, centralized pathology review and tissue-based assays are critical for the success of research projects. During the current SPORE period, the Core has met its milestones and tasks in collecting, processing, storing, and distributing tissues, liquid-based cervical cytology specimens, and biological fluids for translational research. It has done this without compromising patient care. The Pathology Team has also helped SPORE investigators, including the CEP and DRP awardees, with pathology-related research work. We aim to build on our success by addressing logistics challenges during the current SPORE period. Our focus will be on tailoring the Core efforts to individual research project needs, minimizing duplication with existing resources in Cancer Centers and maximizing synergy in tissue banking with other institutional activities at the Johns Hopkins University and the University of Pennsylvania.

Developmental Research Program

Program Co-Directors

• Tian-Li Wang, Ph.D.
• Ronny Drapkin, M.D., Ph.D.

The Developmental Research Program (DRP) is a major focus of the SPORE because it ensures a continuous flow of innovative ideas and activity to stimulate investigation in the context of SPORE translational research. The DRP provides a means to respond to new opportunities and is designed to encourage and facilitate new research efforts. It takes advantage of the broad expertise of researchers at JHU, bringing in investigators from different fields (epidemiology, radiology, immunology, protein chemistry, electrical engineering, molecular biology, and genetics). It provides funds for pilot studies with potential for development into full-fledged translational research projects, collaborations, and new methodologies that could then be integrated into other existing projects. As many as 5 projects will be funded annually.

Career Enhancement Program

Program Co-Directors

• le-Ming Shih, M.D., Ph.D.
• Ronny Drapkin, M.D., Ph.D.

The primary goal of the Penn-JHU Ovarian Cancer SPORE Career Enhancement Program (CEP) is to provide adequate funding and mentorship to promising young investigators to facilitate their early career development. With this support, they can evolve into independent investigators in translational ovarian cancer research. A secondary goal of this program is to provide funds and guidance for established investigators who wish to re-direct their efforts to the area of translational ovarian cancer research.

To ensure the success of the awardees, we will implement a structured mentorship program. The awardees will designate a mentor in the related research field. For projects involving cross-disciplinary studies, co-mentorship is encouraged. In addition, the CEP Co-Directors, who are experts in ovarian cancer research and have extensive experience with mentorship will closely monitor research progress and provide insight and necessary resources to the awardees. The number of faculty and leadership positions in both academia and industry sectors held by previous trainees of the CEP leaders is evidence of the exceptional environment for career development at both UPenn and the Johns Hopkins Medical Institutions. In this program, awardees will use the resources made available to them for the development of a research career in ovarian cancer. Awardees will have access to the scientific Cores of the SPORE (i.e., Biorepository and Pathology Core, and Biostatistics Core). They will automatically be a full member of the Ovarian Cancer SPORE, and will be encouraged to attend monthly Ovarian Cancer SPORE meetings and seminars. In addition, the CEP Co-Directors will provide essential curriculum, meetings, conferences, and educational opportunities to help their career growth flourish. The CEP Co-Directors will build a firm foundation for their future leadership in translational ovarian cancer research.