R01CA258553

Targeting CDK7 in CCNE1-Amplified Ovarian Cancer - Project Abstract

High-grade serous ovarian carcinoma (HGS-OVCA) is the most malignant form of ovarian cancer. Among the most aggressive HGS-OVCA tumors are those that harbor genomic amplification and overexpression of CCNE1, the gene that encodes for cyclin E1, a key cell cycle regulator.

This challenging HGS-OVCA subset carries poor outcomes after standard cytotoxic chemotherapy and is associated with a high proliferative rate, rapid development of platinum resistance, and de novo resistance to poly ADP (ribose) polymerase inhibitors. Despite intense efforts, targeted therapies for the treatment of CCNE1-amplified HGS-OVCA remain elusive, in part due to the paucity of druggable molecular targets. As such, there remains an urgent unmet medical need for the development of new therapies for CCNE1-amplified HGS-OVCA and other cancers marked by CCNE1 overexpression.

Promising preclinical evidence demonstrates that knockdown or inhibition of cyclin-dependent kinase (CDK2), the catalytic kinase partner of cyclin E1, selectively kills CCNE1-amplified ovarian cancer cell lines, highlighting a potential dependency associated with CCNE1 amplification. However, efforts to directly target CDK2 with pharmacological agents have been plagued by difficulties in achieving specificity for CDK2.

We recently employed an alternative strategy of selectively inhibiting CDK7, a key upstream activator of CDK2, to achieve selective killing of CCNE1-amplified ovarian cancer cells. In proof-of-principle studies, YKL-5-124, a new CDK7 inhibitor with superior selectivity over existing inhibitors of its kind, led to pronounced tumor shrinkage in a human xenograft mouse model of CCNE1-amplified HGS-OVCA.

The primary goal of the proposed research is to expand on our preliminary findings by elucidating the underlying principles governing CCNE1-amplified HGS-OVCA sensitivity to CDK7 inhibition. This knowledge will then be leveraged to guide further preclinical inquiry into targeting CDK7 in CCNE1-amplified HGS-OVCA. Herein, we propose to identify (1) HGS-OVCA cancer cells and genetic backgrounds that are sensitive to YKL-5-124; (2) biomarkers that correlate with drug response; and (3) combination strategies that augment or expand drug response (Aim 1).

While YKL-5-124 displays potent in vivo activity in mice, we will continue to optimize these CDK7 inhibitors for improved pharmacokinetics to further the preclinical development of this chemical series (Aim 2). Lastly, we will evaluate YKL-5-124 (or a further in vivo optimized analog) in mouse models of CCNE1-amplified and non-amplified HGS-OVCA (Aim 3).

To accomplish these goals, we have assembled a multi-disciplinary team with expertise in medicinal chemistry (Nathanael Gray, Stanford), cell and systems biology (Caitlin Mills and Peter Sorger, Harvard Medical School), mouse models in ovarian cancer (Panagiotis Konstantinopoulos, DFCI), and translational and clinical ovarian research (Ursula Matulonis, DFCI).

This research describes a new approach to selectively target CCNE1-overexpressing tumors and identifies novel small molecules that will enable the preclinical evaluation of this strategy for the treatment of CCNE1-amplified HGS-OVCA.

The Leland Stanford Junior 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]

Stanford, California 94305 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 368% from $727,068 to $3,403,137.