A strategy to combine pathway-targeted low toxicity drugs in ovarian cancer

• Published in: Oncotarget Vol. 6; no. 31; pp. 31104 - 31118
• Main Authors: Delaney, Joe R, Patel, Chandni, McCabe, Katelyn E, Lu, Dan, Davis, Mitzie-Ann, Tancioni, Isabelle, von Schalscha, Tami, Bartakova, Alena, Haft, Carley, Schlaepfer, David D, Stupack, Dwayne G
• Format: Journal Article
• Language: English
• Published: United States Impact Journals LLC 13.10.2015
• Subjects: Animals; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Antineoplastic Combined Chemotherapy Protocols - toxicity; Autophagy - drug effects; Cell Line, Tumor; Cell Proliferation - drug effects; Dose-Response Relationship, Drug; Female; Humans; Mice, Inbred C57BL; Molecular Targeted Therapy; Neoplasms, Cystic, Mucinous, and Serous - drug therapy; Neoplasms, Cystic, Mucinous, and Serous - metabolism; Neoplasms, Cystic, Mucinous, and Serous - pathology; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - metabolism; Ovarian Neoplasms - pathology; Research Paper; Signal Transduction - drug effects; Time Factors; Tumor Burden - drug effects; Xenograft Model Antitumor Assays; combination therapy; autophagy; adverse events; necramed; ovarian cancer
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.5093

Serous Ovarian Cancers (SOC) are frequently resistant to programmed cell death. However, here we describe that these programmed death-resistant cells are nonetheless sensitive to agents that modulate autophagy. Cytotoxicity is not dependent upon apoptosis, necroptosis, or autophagy resolution. A screen of NCBI yielded more than one dozen FDA-approved agents displaying perturbed autophagy in ovarian cancer. The effects were maximized via combinatorial use of the agents that impinged upon distinct points of autophagy regulation. Autophagosome formation correlated with efficacy in vitro and the most cytotoxic two agents gave similar effects to a pentadrug combination that impinged upon five distinct modulators of autophagy. However, in a complex in vivo SOC system, the pentadrug combination outperformed the best two, leaving trace or no disease and with no evidence of systemic toxicity. Targeting the autophagy pathway in a multi-modal fashion might therefore offer a clinical option for treating recalcitrant SOC.