Johns Hopkins University/University of Pennsylvania SPORE of Ovarian Cancer
Johns Hopkins University
Principal Investigator:
Ie-Ming Shih, MD, PhD
- Principal Investigator Contact Information
- Overview
- Project 2: Optimizing synthetic lethality in high-grade serous ovarian cancer
- Project 3: Overcoming platinum resistance in ovarian cancer through BET inhibition
- Project 4: Exploring the potential of SYK inhibitors to sensitize ovarian cancer to the anti-tumor effects of paclitaxel
- Administrative Core
- Biorepository/Pathology Core
- Biostatistics Core
- Developmental Research Program
- Career Enhancement Program
Principal Investigator Contact Information
Ie-Ming Shih, MD, PhD
Professor of Gynecology and Obstetrics
1550 Orleans St. CRB II 305
Johns Hopkins University
School of Medicine
1550 Orleans Street, Rm 305
Baltimore, MD 21231
(410) 502-7774
Overview
Ovarian cancer is one of the most aggressive cancers in women in the United States and a major cause of cancer morbidity and mortality. The Johns Hopkins-University of Pennsylvania Ovarian Cancer SPORE focuses on reducing ovarian cancer incidence and mortality by translating new laboratory research discoveries made in our institution into improvements in ovarian cancer detection and treatment. This highly translational program contains four hypothesis-driven Research Projects, three Core Resources, the Career Enhancement Program, and the Developmental Research Program. The objective of Project 1 is to determine whether detection of tumor cells from liquid-based cervical fluid specimens, endometrial cavity brushing and/or circulating tumor DNA (ctDNA) from blood can identify early and low-volume ovarian high-grade serous carcinoma (HGSC), the most common type of ovarian carcinoma, or its precursor lesion, serous tubal intraepithelial carcinoma. The goal of Project 2 and Project 3 is to provide critical preclinical and early clinical data for developing more effective combined therapy to treat advanced ovarian HGSC, especially for recurrent diseases. Specifically, Project 2 is to optimize synthetic lethality in high-grade ovarian serous ovarian cancer by using ATR inhibitor and PARP inhibitor. Project 3 based on a recent discovery made by our team proposes to apply BET inhibitors for overcoming platinum resistance. Project 4 aims to determine that inhibition of Spleen Tyrosine Kinase (SYK) activity sensitizes ovarian cancer cells to the cytotoxic effect of paclitaxel, and determine if SYK inhibitor represents a promising new agent to be combined with (weekly) paclitaxel for the treatment of advanced ovarian cancer.
These Projects are supported by an Administrative Core, a Biorepository/Pathology Core, and a Biostatistics Core. Finally, the Career Enhancement and Developmental Research Programs comprise pipelines of human capital and innovative ideas, respectively, which will fuel future SPORE advances. This application is strongly supported by institutional commitment to ensure its success.
Project 2: Optimizing synthetic lethality in high-grade serous ovarian cancer
Project Co-Leaders:
Fiona Simpkins, MD
Ronny Drapkin, MD, PhD
Eric J Brown, PhD
Ovarian high-grade serous cancer (HGSC) is the most lethal gynecological malignancy. More than 80% of HGSC patients recur after standard chemotherapy. We have identified a novel and highly active genotoxic therapy by co-inhibiting poly-ADP ribose polymerase (PARP) and ATR checkpoint kinase. Combination PARP inhibition with ATR inhibition (PARPi-ATRi) synergizes to specifically target and kill ovarian HGSCs harboring common HGSC-associated alterations, e.g. homologous recombination (HR) deficiency and Cyclin E overexpression. Our preliminary studies show that PARPi-ATRi in combination is especially effective in killing tumor cells with these alterations and even causing regression of HR-deficient and Cyclin E overexpressing ovarian HGSCs. In the clinic, PARP inhibition (PARPi) treatment alone for ovarian cancer results in partial tumor regression and rarely complete responses with the ultimate emergence of drug resistance. This proposal addresses this urgent clinical need by using a potent new combination treatment to convert partial responses with PARPi monotherapy into complete and durable tumor regression.
For these studies, we have developed: 1) >60 PDX models representing the clinically most common and challenging conditions to treat including: HR-deficient, PARPi-resistant and Cyclin E overexpressing ovarian HGSCs with differing platinum sensitivities, 2) a novel PARPi tracer that will be tested as a predictive and pharmacodynamic marker to guide patient selection for PARPi therapies, 3) advanced proteomic methods to detect both global-tumor and replication fork-specific responses to treatment. We hypothesize that dual inhibition of PARP and ATR will increase the frequency of complete tumor regression in ovarian cancer compared to PARPi monotherapy. The proposed studies herein will test the efficacy of PAPR inhibitor (PARPi, olaparib), by combination with ATR inhibitor (ATRi, AZD-6738) in the first clinical trial in ovarian cancer supported by our preclinical data. Secondly, we will identify dosing schedule strategies to minimize drug toxicity without compromising efficacy for PARPi-ATRi in PDX models. Combination PARPi-ATRi has shown efficacy and tolerability in early phase IB trials, but ways to decrease toxicity are important to optimize quality of life for these patients. Finally, we will perform genomic and proteomic studies to identify biomarkers of PARPi-ATRi response for evaluation in future clinical trials. Our Hopkins—PENN SPORE team is comprised of: expert clinical trialists, translational scientists with preclinical models and drug optimization expertise, molecular biologists with expertise in DNA replication stress, SPORE Cores such as Pathology that will promote optimal patient tissue procurement and processing and Biostats to oversee data analysis. Thus, our team is well positioned for success with realizing Project 2 goals.
Specific Aims
Aim 1: To examine the efficacy of olaparib-AZD-6738 (ATRi) in the first clinical trial in ovarian cancer.
Aim 2: To identify dosing schedule strategies to minimize drug toxicity without compromising efficacy for PARPi-ATRi in PDX models.
Aim 3: To identify biomarkers of PARPi-ATRi response by molecular profiling.
Project 3: Overcoming platinum resistance in ovarian cancer through BET inhibition
Project Co-Leaders:
Rugang Zhang, PhD
Lainie Martin, MD
The overall goal of this proposal is to determine whether the bromodomain and extra-terminal (BET) protein BRD4 is a promising therapeutic target for delaying and/or overcoming resistance to platinum-based ovarian cancer standard of care. Chemoresistance is a major cause of the high mortality of ovarian cancer and in particular in the most common high-grade serous carcinoma (HGSC). Substantial evidence suggests that cells with cancer stem-like cells (CSC) characteristics contribute to chemotherapy resistance. Putative ovarian cancer CSCs are typically characterized by increased aldehyde dehydrogenase (ALDH) activity. This is a hypothesis-driven translational study, and the findings will be pivotal for evaluating whether BET inhibitors in combination with platinum represents an effective approach for overcoming platinum resistance by suppressing ALDH activity in ovarian cancer CSCs. We will collaborate with Incyte, Inc. to use their BET inhibitor INCB57643 that is proven safe in patients. Thus, the BET inhibitor is readily available for immediate translation in ovarian cancer. The proposed studies are based on our recent findings established that inhibition of BRD4 activity by BET inhibitors is sufficient to eradicate ALDH positive CSCs. Our central hypothesis is that platinum resistance can be overcome through eliminating ALDH positive cancer stem-like cells by targeting BRD4 using clinical applicable small molecule BET inhibitor INCB57643. Three specific aims are proposed:
Specific Aims
Aim 1: To explore the combination of BET inhibitor INCB57643 and carboplatin in patients with HGSC in a Phase 1 clinical trial.
Aim 2: To investigate a combined therapeutic strategy of targeting BRD4 by BET inhibitor INCB57643 and carboplatin in HGSC cell lines and patient-derived xenografts (PDX).
Aim 3: To identify companion biomarkers that correlate with response to BET inhibitor INCB57643 and carboplatin combination in HGSCs.
The proposed studies are highly innovative because they challenge current research/clinical paradigms, contribute to new concepts for epigenetic therapeutics by combining BET inhibitors and platinum, and utilize innovative methods to explore new intervention strategies for chemotherapy resistance in ovarian cancer. The proposed studies are of high impact because these studies will develop therapeutic strategies with a durable therapeutic outcome by overcoming platinum resistance through eradicating cancer stem-like cells, a major challenge in the clinical management of ovarian cancer.
Project 4: Exploring the potential of SYK inhibitors to sensitize ovarian cancer to the anti-tumor effects of paclitaxel
Project Co-Leaders:
Ie-Ming Shih, MD, PhD (Co-leader)
Deborah Armstrong, MD (Co-leader)
Stephanie Gaillard, MD, PhD (Co-leader)
The purpose of this proposal is to provide critical pre-clinical and early phase clinical evidence to determine whether the Spleen Tyrosine Kinase (SYK) is a promising therapeutic target in ovarian cancer. We have previously compared the proteomes of primary and recurrent/post-chemotherapy ovarian high-grade serous carcinoma (HGSC) tissues from the same patients. Among the preferentially expressed proteins in recurrent HGSCs, a non-receptor tyrosine kinase, SYK, was prioritized for study because small molecule inhibitors of SYK including fostamatinib are available for pre-clinical testing and clinical trials. We were able to validate overexpression of SYK and its active (auto)phosphorylated form in recurrent HGSC after carboplatin and paclitaxel treatment compared to treatment naive tumors. SYK inhibition exhibited a synergistic cytotoxic effect with paclitaxel, docetaxel, and vinorelbine, all of which target the microtubule network. Paclitaxel resistant ovarian cancer cells exhibit higher levels of SYK expression than their carboplatin-resistant counterparts. Our preliminary phosphoproteomic analysis revealed tubulins and several microtubule-associated proteins as SYK substrates in ovarian cancer cells. Phosphorylation of these proteins has been shown to increase microtubule dynamics, a process antagonizing the microtubule-stabilizing effect of paclitaxel. In a mouse tumor xenograft model, the combination of R406 (the active form of fostamatinib) and paclitaxel significantly suppressed tumor growth without overt signs of toxicity. Our pre-clinical studies support a novel hypothesis that SYK activity is required for paclitaxel resistance and that SYK inhibition sensitizes HGSC to the cytotoxic effect of paclitaxel. Therefore, SYK inhibitors represent a promising new strategy to treat ovarian cancer.
To test the above hypotheses, we propose the following Specific Aims:
Aim 1: Phase I/Ib clinical trial of combined fostamatinib and paclitaxel in ovarian cancer.
Aim 2: Characterize the prioritized SYK substrates discovered in ovarian cancer cells.
Aim 3: Assess the efficacy of SYK-based combination therapy in mouse models.
Administrative Core
Core Directors:
Ie-Ming Shih, MD, PhD
Ronny Drapkin, MD, PhD
Deborah Armstrong, MD
Robert Burger, MD
Tian-Li Wang, PhD
Under the direction of the Director, Dr. Ie-Ming Shih, the Core will provide the administration, management, and coordination of all projects and cores. In addition, the Core will coordinate activities of the review committees that oversee SPORE research activities and program development and will prepare annual scientific reports and budgetary information. Dr. Ronny Drapkin will oversee administrative aspects of the University of Pennsylvania’s SPORE research activities and collaborate and coordinate with Dr. Shih regarding overall SPORE operations. Dr. Deborah Armstrong and Dr. Robert Burger serve as the Clinical Research Co-Directors (Core Co-Directors). They oversee patient identification, enrollment, and patient monitoring in the clinical component of the SPORE at each site (JHU and Penn, respectively). They will be assisted by a Clinical Research Coordinator and Data Safety Monitoring Boards. These tasks are critical for effective use of patient resources and for ensuring the safety and confidentiality of patients enrolled in translational projects. Thus, each component of the Core is key in the management and oversight of all SPORE activities.
Biorepository/Pathology Core
Core Directors:
Ronny Drapkin, MD, PhD
Amanda Nickles Fader, MD
Tian-Li Wang, PhD
Daniel J. Powell Jr., PhD
The Biorepository/Pathology Core will collect and distribute clinically annotated human biospecimens related to ovarian cancer and will provide pathologic expertise and support for tissue-based analyses for investigators in the Johns Hopkins-University of Pennsylvania (UPENN) Ovarian Cancer SPORE. The main resource and operation of this Core will be based on the current Gynecologic Cancer Biorepository (GCB) Bank that has been a co-joint operation among the JHU Oncology Center, the Kelly Gynecologic Oncology Service in the Department of Gynecology and Obstetrics, and the Division of Gynecologic Pathology. The GCB bank was established in 2000 and expanded through the support of a US DoD-sponsored program project and subsequently by the DoD-sponsored Ovarian Cancer Consortium Program. In addition, the Cellular Therapy Tissue Facility (CTTF) at UPENN will provide all tissue procurement and processing for Project 3 (at UPENN) and will procure and process tissue to support Projects 1 and 4 at JHU. The CTTF collects and processes fresh tumor tissue acquired directly from the operating rooms at the Hospital of the University of Pennsylvania and Pennsylvania Hospital, as well as from external institutions, including Chester County Hospital. Tissue will be shared between JHU and UPENN, as well with other collaborating institutions. Thus, the Ovarian Cancer SPORE
Biorepository/Pathology Core will incorporate and build on a pre-existing infrastructure. In the last few years, the Repository has been expanded to include expert diagnostic pathology and molecular pathology consultation to investigators, including guidance for quantitative digital image analyses-guided molecular studies of tissues. Specimens are collected under the supervision of pathologists with expertise in gynecologic pathology, in close collaboration with gynecologic oncology surgical colleagues. Clinical information for subjects enrolled in our clinical protocols is entered into a password-protected web-based tracking system, which follows the recommendations of the National Research Council. A review mechanism is in place for prioritization of distribution of requested resources to investigators within and external to this Ovarian Cancer SPORE.
Biostatistics Core
Core Directors:
Hongkai Ji, PhD
Peng Huang, PhD
The Biostatistics Core Resource will provide comprehensive biostatistics and bioinformatics consultation and collaboration to all Research Projects in the proposed Johns Hopkins Ovarian Cancer SPORE. Core members will work with project investigators across a wide spectrum of activities, encompassing data acquisition (including study design, feasibility of objectives, availability of public-access genomic information, and data storage), statistical quality control (including artifact detection and preprocessing of data from genomic technologies), data analysis (including visualization, biostatistical modeling, and assistance with manuscript writing), and development of innovative customized biostatistical methodologies and tools if required by specific projects. The proposed Ovarian Cancer SPORE Biostatistics Core is housed in the Division of Oncology Biostatistics and Bioinformatics of the Department of Oncology, an active and committed group of biostatistics and bioinformatics faculty members, with access to state-of-the art equipment and a broad range of expertise. This Core resource builds on expertise gained by Core members who actively participate in other SPOREs at Johns Hopkins. Core members have a strong commitment to this SPORE, stemming from: a) a history of collaboration with the investigators on this other research projects in ovarian cancer, b) an active and independently funded agenda of synergistic projects in cancer genetics and genomics, and c) a demonstrated interest and understanding of both the biological and analytical questions and challenges. All proposed Projects are anticipated to make use of this Resource.
Developmental Research Program
Program Directors:
Ronny Drapkin, MD, PhD
Richard Roden, Phd
The Developmental Research Program (DRP) is an important component of the SPORE and critical to the long-term fight against ovarian cancer. It provides an avenue for soliciting new research ideas and for developing innovative high-risk, but high-impact projects to stimulate ovarian cancer research in the context of the SPORE. Pilot studies provide investigators with the resources to conduct translational research consistent with the SPORE’s objectives. The selection process will be made by the DRP Scientific Review Committee, which is composed of accomplished investigators who have demonstrated outstanding track records in cancer research. The recipients will be required to submit annual progress report(s) that will be reviewed by the committee. This program encourages participation from a broad range of investigators at Johns Hopkins University (JHU), University of Pennsylvania (PENN), the Wistar Institute, and Howard University by providing support for pilot projects with the potential to develop into more fully developed translational projects. It also encourages and facilitates the development of new research directions, methodologies, and collaborations. In addition, a combined total of $300,000 annually is available from the institutional match funds together with the SPORE support, to fund as many as 6 projects at the funding level of $50,000 per year.
Specific Goals
Aim 1: To provide initiating funds for novel explorations related to translational ovarian cancer studies.
Aim 2: To integrate the awardee into the SPORE community by participation in monthly meetings, group communications, and opportunities for expanded funding and for collaborations.
Aim 3: To review progress and recommend avenues for the continuation of successful projects.
Career Enhancement Program
Program Directors:
Ie-Ming Shih, MD, PhD
Ronny Drapkin, MD, PhD
The Career Enhancement Program (CEP) of the Ovarian Cancer SPORE intends to attract and stimulate new investigators, including women, minorities, and individuals with disabilities to carry out translational research related to ovarian cancer and provide mentorship. The program director, Dr. Burger, and the co-director, Dr. Shih, will solicit applications and coordinate selection process. Candidates submit an application and are evaluated through a careful selection process involving a career enhancement committee as well as the SPORE steering committee. The recipients will be required to present their progress twice a year and submit annual progress report subject to the aforementioned review process. In addition to the requested funding ($50,000) from the SPORE program, a total annual matching fund of $150,000 will be provided by the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins and the Department of Gynecology/Obstetrics at University of Pennsylvania. Those supports allow us to fund 2-3 career awards at funding levels of $50,000 to $100,000 each year. It is expected that the CEP will play an important role in the recruitment and development of a cadre of outstanding translational scientists and future leaders in the ovarian cancer research field. At the same time, these new investigators will bring their own unique expertise and innovations to this Ovarian Cancer SPORE program.
Specific Goals
Aim 1: To attract, select, and mentor promising new investigators with a special emphasis on recruiting qualified women, minorities, and individuals with disabilities.
Aim 2: To develop and support the awardee’s rigorous and innovative translational research projects focusing on various topics related to ovarian cancer.