R01CA257507

New Approaches to Modeling and Targeting Cyclin E-Amplified High-Grade Serous Tubo-Ovarian Carcinoma - Project Summary

Nearly all ovarian cancer deaths result from platinum-resistant high-grade serous tubo-ovarian carcinoma (HGSC), which typically responds poorly to PARP inhibitors, other "targeted therapies," conventional chemotherapy, and/or immune checkpoint blockade.

Approximately 20% of HGSC is driven by CCNE1 amplification (CCNE1AMP), which almost always leads to platinum resistance. This MPI application joins experts in cancer biology/signal transduction/mouse modeling (Neel) and HGSC genomics/therapeutics (Levine) with the overall objective of improving treatment of this poorly responsive subgroup.

We contend that achieving this goal will require detailed analysis of sophisticated, genetically informed, immune-competent models of CCNE1AMP HGSC. To this end, we developed a novel, mouse fallopian tube epithelial (FTE) organoid platform that can be used for rapid modeling of combinations of the genetic defects seen in human HGSC, as well as organoid and patient-derived xenograft (PDX) models of normal FTE and human CCNE1AMP HGSC.

In work under review, we found that BRCA1-deleted, CCNE1-overexpressing (CCNE1OE), and PTEN/NF1-deleted FTE organoids differ in proliferation/differentiation, cytokine/chemokine secretion, and drug response in vitro, and evoke tumors with distinct kinetics, transcriptomes, and tumor immune microenvironments (TMES) upon orthotopic injection (ovarian bursa) into syngeneic mice.

Based on this information, we devised a chemo-immunotherapy regimen that yields T cell-dependent, durable, apparently curative, complete responses (CR) in a highly aggressive TP53-/-;CCNE1OE;AKT2OE;KRASOE HGSC model.

We now propose to:
(I) Clarify the mechanistic efficacy of this combination regimen,
(B) Determine the effects of other mutational events that co-occur frequently with CCNE1AMP on the phenotype of TP53-/-;CCNE1OE FTE in vitro and in vivo, including whether our combination regimen is broadly efficacious in CCNE1OE HGSC, and
(C) Assess the relevance of these findings in human organoid and PDX models of CCNE1AMP HGSC.

New York University

TO DEVELOP THE MEANS TO CURE AS MANY CANCER PATIENTS AS POSSIBLE AND TO CONTROL THE DISEASE IN THOSE PATIENTS WHO ARE NOT CURED. CANCER TREATMENT RESEARCH INCLUDES THE DEVELOPMENT AND EVALUATION OF IMPROVED METHODS OF CANCER TREATMENT THROUGH THE SUPPORT AND PERFORMANCE OF BOTH FUNDAMENTAL AND APPLIED LABORATORY AND CLINICAL RESEARCH. RESEARCH IS SUPPORTED IN THE DISCOVERY, DEVELOPMENT, AND CLINICAL TESTING OF ALL MODES OF THERAPY INCLUDING: SURGERY, RADIOTHERAPY, CHEMOTHERAPY, AND BIOLOGICAL THERAPY INCLUDING MOLECULARLY TARGETED THERAPIES, BOTH INDIVIDUALLY AND IN COMBINATION. IN ADDITION, RESEARCH IS CARRIED OUT IN AREAS OF NUTRITIONAL SUPPORT, STEM CELL AND BONE MARROW TRANSPLANTATION, IMAGE GUIDED THERAPIES AND STUDIES TO REDUCE TOXICITY OF CYTOTOXIC THERAPIES, AND OTHER METHODS OF SUPPORTIVE CARE THAT MAY SUPPLEMENT AND ENHANCE PRIMARY TREATMENT. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO EXPAND AND IMPROVE THE SBIR PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.395 - Cancer Treatment Research

National Cancer Institute (NCI) [HHS - NIH]

New York, New York 10016 United States

Single Zip Code

Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-19-056)

Amendment Since initial award the total obligations have increased 391% from $703,320 to $3,453,304.