Most ovarian cancer deaths (~70%) occur in patients with advanced, high-grade serous ovarian cancer (HGS-OvCa). Standard treatment for this disease, which includes surgery plus chemotherapy, yields long-term (5+ year) remissions in only around 30% of patients. The majority of deaths from HGS-OvCa are caused when the disease eventually fails to respond to chemotherapy. It is clear, therefore, that in order to improve patient outcomes, we must develop chemotherapeutic strategies that more consistently and durably eliminate disseminated, recalcitrant disease. Unfortunately, doing this is a challenge, as we know that individual tumors can activate a range of growth- and survival-promoting processes that allow them to survive the otherwise lethal effects of chemotherapy.
Recently, my laboratory developed a pair of companion methods that we collectively refer to as “Oncopathway Profiling”. These methods enable us, for the first time, to rapidly and systematically identify the specific processes that cancer cells use to overcome the toxicity of chemotherapies and then design new therapies that reverse these processes, synergistically enhancing chemotherapeutic efficacy. Already, we have demonstrated the power of Oncopathway Profiling in studies involving a range of diverse cancer types and drugs, studies which have led to both new insights into the biological mechanisms governing chemotherapeutic response as well as the design of improved combination therapies with enhanced selectivity and potency.
In this proposal, we describe the use of Oncopathway Profiling to identify combination therapies to improve the responses of HGS-OvCa patients to both existing, approved “cytotoxic” chemotherapeutics as well as a set of emerging new “targeted” therapies. We describe a pipeline for identifying key biological mechanisms governing response to these drugs, followed by the in-depth credentialing of multiple strategies to reverse these mechanisms and ultimately the validation of these strategies in HGS-OvCa cell lines and animal models. This work extends from my laboratory’s strong interests in women’s cancers and leverages our existing collaborations with well-established ovarian cancer clinicians and researchers at Duke University. If successful, the work described in this proposal will serve as a springboard for the clinical translation of new, improved therapeutic strategies to improve the outcomes of patients with HGS-OvCa.