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 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 models 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.