Johns Hopkins University/University of Pennsylvania SPORE of Ovarian Cancer
Johns Hopkins University
Principal Investigators:
Ie-Ming Shih, MD, PhD
Ronny Drapkin, MD, PhD
- Principal Investigators Contact Information
- Overview
- Project 1: Diagnosis Of Ovarian Cancer Precursors And Incipient Carcinoma
- Project 2: Targeting CCNE1 Overexpression In High-Grade Serous Ovarian Cancer
- Project 3: Investigating New Treatment Approaches Based On DNA Repair Vulnerability In ARID1A Mutated Type I Ovarian Cancer
- Administrative Core
- Biorepository/Pathology Core
- Computational and Biostatistics Core
- Developmental Research Program
- Career Enhancement Program
- Institutional SPORE Website
Principal Investigator Contact Information
Ie-Ming Shih, MD, PhD
Professor of Gynecology and Obstetrics
Johns Hopkins University
School of Medicine
1550 Orleans St. CRB II 305
Baltimore, MD 21231
(410) 502-7774
Ronny Drapkin, MD, PhD
Franklin Payne Professor
University of Pennsylvania
421 Curie Blvd., Rm. 1215
Biomedical Research Building
Philadelphia, Pennsylvania, 19104
(215) 746-3973
Overview
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. 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.
Project 1: Diagnosis Of Ovarian Cancer Precursors And Incipient Carcinoma
Project Co-Leaders:
Ie-Ming Shih, M.D., Ph.D., Clinical Co-Leader
Nickolas Papadopoulos, Ph.D., Basic Co-Leader
Ronny Drapkin, M.D., Ph.D., Basic Co-Leader
The current strategy for identifying HGSC precursors in the fallopian tube relies on a structure assessment of the fallopian tube bordering fringe called the fimbria. This 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 the occurrence of one or more extra missing chromosomes and DNA methylation (a chemical reaction in which a small molecule is added to DNA) 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 abnormal cervical tissue growth. 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.
Aim 1: Assess the performance of brushing in prospective risk-reduction salpingo-oophorectomy specimens from high-risk women.
Aim 2: Elucidate pathogenesis in potentially aggressive STIC subtypes.
Project 2: Targeting CCNE1 Overexpression In High-Grade Serous Ovarian Cancer
Project Co-Leaders:
Fiona Simpkins, M.D., Clinical Co-Leader
Erick Brown, Ph.D., Basic Co-Leader
High-grade serous carcinomas (HGSCs) exhibit significant gene mutations, with CCNE1 amplification being common and linked to platinum resistance and poor survival. The principal investigators 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 severe toxic effects to the kidney, liver, central nervous system and cardiac tissue 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 patient-derived xenograft (PDX) and artificial organ models. 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.
Aim 1: Development of Cyclin E as a biomarker of response for WEE1i.
Aim 2: Characterize WEE1i resistance and test new a combination strategy to overcome it.
Aim 3: Identify mechanistically relevant biomarkers of WEE1i and WEE1-ATRi response.
Project 3: Investigating New Treatment Approaches Based On DNA Repair Vulnerability In ARID1A Mutated Type I Ovarian Cancer
Project Co-Leaders:
Stephanie Gaillard, M.D., Ph.D.
Tian-Li Wang, Ph.D.
Philipp Oberdoerffer, Ph.D.
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.
Aim 1. Understanding how ARID1A mutation in ovarian cancer cells confers sensitivity to TMZ/PARPi combination therapy
Aim 2. To evaluate the clinical efficacy of the combination of TMZ and the PARPi, senaparib, in ARID1Amut ovarian clear cell and endometrioid carcinoma in a Phase 2 clinical trial
Administrative Core
Core Directors:
Ie-Ming Shih, MD, PhD
Stephanie Gaillard, M.D., Ph.D.
Ronny Drapkin, MD, PhD
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.
Biorepository/Pathology Core
Core Directors:
Amanda Fader, M.D.
Tian-Li Wang, Ph.D.
Ronny Drapkin, M.D., Ph.D.
The Biorepository/Pathology Core provides all investigators participating in this SPORE and external collaborators with the opportunity to study human bio-specimens and the origin/nature of the disease being researched. The availability of well-characterized, high-quality human tissues and biological fluids is pivotal to the projects within this SPORE. Using these specimens for a centralized pathology review and tissue-based analysis 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.
Computational and Biostatistical Core
Core 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.
This Core will enhance the ability to reproduce all clinical and laboratory studies through the strict and unbiased application of the scientific method 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 our ability to distribute information on 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.
Developmental Research Program (DRP)
Program Directors:
Tian-Li Wang, Ph.D.
Ronny Drapkin, M.D., Ph.D.
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.
Aims:
- To provide initiating funds for novel explorations related to translational ovarian cancer studies.
- To integrate the awardee into the SPORE community by participation in monthly meetings, group communications, and opportunities for expanded funding and for collaborations.
- To review progress and recommend avenues for continuation of successful projects.
Career Enhancement Program (CEP)
Program Directors:
Ie-Ming Shih, M.D., Ph.D.
Ronny Drapkin, M.D., Ph.D.
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.
Specific Aims:
- To recruit, support, and develop talented investigators as SPORE Career Enhancement Program Scholars to conduct translational research focused on GYN cancers.
- To specifically recruit, support, and develop talented women and underrepresented minority investigators as SPORE Career Enhancement Program Scholars to conduct translational research and build careers focused on GYN cancers.
- To provide outstanding translational research mentorship, training, and opportunities for investigators to develop sufficient knowledge, skills, and expertise to successfully pursue independent translationally oriented scholarly research careers focused on GYN malignancies.
- To provide broad career mentoring, and support development of research and organizational skills to ensure the CEP scholars are optimally prepared to engage and benefit from the interaction with the institutional, academic, pharmaceutical, research, funding, regulatory and patient-based communities.
- To expand and enhance the cadre of investigators at JHU and PENN focused on innovative GYN Cancer Research and to develop new investigators with all the competencies required to successfully initiate and conduct independent R01 or SPORE-type projects focused on GYN cancer research.
Institutional SPORE website:
Ovarian Cancer Specialized Program of Research Excellence (SPORE) | Johns Hopkins Medicine