Specialized Ovarian Cancer Research (SPORE)
Johns Hopkins Medicine and the University of Pennsylvania have been awarded the prestigious Specialized Programs of Research Excellence (SPORE) grant by the National Cancer Institute for furthering translational ovarian cancer research. This grant (2024-2029) will offer new opportunities for ovarian cancer patients seeking innovative clinical trials and new diagnostic tools for early detection of ovarian cancer in women.
On this page:
Research Objectives | Current Projects | Support Cores | Career Development Programs | Our Team
Research Objectives
The primary goal of our partnership is to translate our recent laboratory research discoveries into improvements in ovarian cancer diagnosis and treatment.
Ovarian cancer is one of the most aggressive cancers in women in the United States. It’s often detected in its advanced stage, making it difficult to treat and a major cause of cancer morbidity and mortality. Our team will evaluate innovative approaches for early diagnosis through the development of more effective diagnostic tools and investigate novel therapies that will minimize chemotherapy resistance and reduce recurrence after regular treatment. Clinical trials will support this research, and we are currently accepting eligible applicants.
This SPORE is led by Dr. Ie-Ming Shih, the Richard W. TeLinde Distinguished Professor in the Department of Gynecology and Obstetrics at Johns Hopkins Medicine, and Dr. Ronny Drapkin, the Franklin Payne Professor in the Department of Obstetrics and Gynecology at the University of Pennsylvania.
Research Program Structure
This translational program is composed of three hypothesis-driven research projects, three shared core resources, the Career Enhancement Program, and the Developmental Research Program. Below we provide a synopsis of our program goals and structure. 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.
Current Projects
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Team Member Role Dr. Ie-Ming Shih Co-Leader Dr. Nickolas Papadopoulos Co-Leader Dr. Ronny Drapkin 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 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.
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Team Member Role Dr. Fiona Simpkins Co-Leader Dr. Erick Brown 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, and 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 measure tumor CCNE1 copy number and identify sensitivity biomarkers using whole genome cfDNA analysis (DELFI), whole exome, and RNA sequencing. Although WEE1i monotherapy is expected to be effective, we hypothesize that resistance will emerge, and 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 recruited to replication forks following WEE1i and ATRi treatment to 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.
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Team Member Role Dr. Stephanie Gaillard Co-Leader Dr. Tian-Li Wang Co-Leader Dr. Philipp Oberdoerffer 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.
Cores
These projects are supported by an administrative core, a biorepository/pathology core and a computational/biostatistics core.
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Team Member Role Dr. Ie-Ming Shih Co-Director Dr. Stephanie Gaillard Co-Director Dr. Ronny Drapkin Co-Director 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 overall program, ensuring 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.
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Team Member Role Dr. Amanda Fader Co-Director Dr. Tian-Li Wang Co-Director Dr. Ronny Drapkin Co-Director The Biorepository/Pathology Core provides project-driven human bio-specimen service and pathology consultation to all investigators participating in this SPORE and 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 without compromising of 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 maximize synergy in tissue banking with other institutional activities at the Johns Hopkins University and the University of Pennsylvania.
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Team Member Role Dr. Peng Huang Co-Director Dr. Leslie Cope Co-Director 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
Career Enhancement and Developmental Programs
We have also established Career Enhancement and Developmental Research Programs to help fuel future SPORE advances.
Interested in submitting a project? Read our application guidelines and learn how to apply here.
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Team Member Role Dr. Ie-Ming Shih Co-Director Dr. Ronny Drapkin Co-Director The Career Enhancement Program provides funding and support to promising young investigators to help facilitate their early career development and build a firm foundation for their future leadership in the translational ovarian cancer research field. Secondarily, the program will also support established investigators who want to redirect their research efforts to translational ovarian cancer research.
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Team Member Role Dr. Tian-Li Wang Co-Director Dr. Ronny Drapkin Co-Director The Developmental Research Program provides funding for pilot studies with potential for development into large-scale translational research projects, collaborations, and new methodologies that may be integrated into other existing projects. This program is a major focus of the SPORE because it encourages the flow of innovative ideas and new research efforts that may emerge within the context of SPORE research.
Program Leadership
Shih, Ie-Ming, M.D., Ph.D.
Johns Hopkins Medicine
Drapkin, Ronny, M.D., Ph.D.
University of Pennsylvania