Project Summary/Abstract
Ovarian cancer is the fifth leading cause of cancer deaths overall in women. The most recent estimates
indicate that over 20,000 new cases will be diagnosed this year and nearly 14,000 women will die of the
disease in the US in 2019 alone. The platinum-based standard of care cytotoxic regimen has remained largely
stagnant for the last 15 years and recurrent disease is frequently platinum-resistant. Despite some recent
success using molecular targeted agents and maintenance therapies (such as PARP inhibitors), the genetic
complexity and lack of common molecular drivers make predicting patient responses difficult. Additionally, in
relapsed patients, molecular changes induced by cancer therapies are multifaceted. Combining multiple drugs
to treat ovarian cancer may be the most direct path to overcoming this intra-tumoral heterogeneity and
acquired resistance to achieve more durable clinical responses. In an effort to capitalize on drugs that are
approved and show patient benefit, this proposal seeks to identify compounds that can sensitize cells to
apoptosis when combined with one of three drugs that act as cornerstones in ovarian cancer therapy:
carboplatin, the PARP inhibitor olaparib, and doxorubicin. In the first aim a novel high-throughput screening
platform called high-throughput dynamic BH3 profiling, will be used to identify whether a 24-hour ex vivo
chemical treatment sensitizes tumor cells to mitochondrial mediated apoptosis. This will be performed using
three ovarian cancer models: (1) freshly isolated tumor cells from primary patient ascites fluid, (2) organoid
cultures derived from primary tumors, and (3) ovarian tumor cell lines. Preliminary data indicates that BH3
mimetics in combination with the standard of care drugs can increase apoptotic induction. In the second aim,
the mechanism of drug-induced BH3 mimetic sensitivity will be investigated on the cellular, mitochondrial, and
molecular level to determine which cellular contexts are likely to benefit from specific BH3 mimetic
combinations. In the third and final aim compounds identified that increase apoptotic induction in combination
with each of the three standard of care drugs will be tested in recently developed patient-derived luciferized
tumor xenograft models of ovarian cancer. This will provide in vivo validation of the ability of specific drug
combinations to cause tumor regression. This innovative approach offers both the potential to identify effective
combinations to use in the platinum-sensitive, PARP-sensitive, and platinum-resistant settings, and the
opportunity to determine molecular features that can identify populations that would benefit from these
combinations. Supplementing the research component of the proposal with select courses and workshops,
engagement in research meetings and seminars, and participation in scientific conferences will ensure an
understanding of current concepts and techniques, constant feedback regarding the project's results and
progress, and enhanced exposure to more translational work. Collectively, the research and training plan will
provide a strong foundation upon which to build a career as a productive, independent cancer researcher.