Ovarian cancer incidence and mortality have remained essentially unchanged during the modern era of cancer treatment. Targeted therapy has emerged as a promising strategy in diverse cancer types, including ovarian cancers. The use of PARP inhibitors in a second-line maintenance setting has provided a therapeutic opportunity, particularly in the patient population that have BRCA mutations. However, responses to targeted therapies such as PARP inhibitors are usually brief, even when patients initially respond to targeted therapy. Therefore, we need therapeutic options that can lead to strong and durable responses in ovarian cancer patients. There is also a critical unmet need to extend successful therapies to ovarian cancer patients without BRCA mutations. Combination drug therapy will be required to improve patient outcomes through overcoming or preventing emergence of drug resistance. The discovery of effective drug combinations is a daunting task due to the complexity of biological processes that mediate drug response and resistance. Here, we combine our well-established high-throughput data generation and bioinformatic pipelines to discover novel combination therapies that can revolutionize ovarian cancer treatment. While we have previously identified combination therapies and translated the combination therapy to clinical trials, approaches to the development of combination therapies are hindered by the lack of effective platforms including systems and computational biology approaches. These approaches will be needed to allow us to move beyond candidate approaches to truly integrated analysis.
Our strategy is to apply advanced experimental techniques to monitor changes in cells after therapy, and then use this information to build mathematical models of tumor cell events that can predict how a specific tumor responds to a new therapy. We test the most promising predictions in cell cultures and mouse models of drug-resistant ovarian cancer. We aim to nominate novel and effective drug combinations as candidates for clinical trials at MD Anderson Cancer Center (MDACC) through the SPORE and Moon Shot program. To address these major challenges in ovarian cancer treatment, we have assembled an interactive team of world leading scientists with diverse and complementary expertise in ovarian cancer as well as other diseases from MDACC and Baylor College of Medicine. Our team encompasses experts in ovarian cancer biology and therapeutics, computational systems biology, and patient care. Importantly, we have extensive experience in leveraging funding support to create teams that are able to compete for sustainable funding, a key goal of this proposal.