Combination Of Autophagy Selective Therapeutics (COAST) in Serous Ovarian Cancer

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Abstract Despite being a relatively rare form of cancer, ovarian cancer is the 5th leading cause of cancer deaths in women (ACS). The complex genetics and lack of targetable alterations yield a current treatment regimen of platinum and taxane agents with surgical debulking. No changes in targeted therapy for serous ovarian cancer have occurred in the last 40 years, with the lone and recent exception of PARP inhibitors. The research paradigm of finding a promising oncogene to target with single-drug adjuvant therapy has failed every test in clinical trials. This needs to change. We previously established that 5-drug combination therapy with autophagy drugs is non- toxic and induces complete remission in patient-derived-xenograft platinum-resistant ovarian cancer mouse models. However, an ethical human trial would require a refinement of this combination to convincingly show which combination is minimally required for full efficacy while remaining safe. We propose to study such combinations in an OVCAR3 nude mouse model for efficacy, and a mixed-background B6D2F1 mouse model for safety. In vivo fluorescence will track tumor progression. A xenograft of cells from a patient with recurrent disease following PARP inhibition will be tested. Safety criteria will include mouse weight, food consumption, H&E pathology on all organs, blood biochemistry, and blood cell counts. These will serve as the final mouse model data prior to human trials in ovarian cancer. To further ascertain if the benefits of autophagy-targeting drugs are amenable to other cancers containing autophagy deficiency, such as triple negative breast cancer and p53 mutant endometrial cancer, subcutaneous xenografts of these solid tumors will additionally be tested.