A strategy to combine pathway-targeted low toxicity drugs in ovarian cancer
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Joe R. Delaney1, Chandni Patel1, Katelyn E. McCabe1, Dan Lu1, Mitzie-Ann Davis1, Isabelle Tancioni1, Tami von Schalscha1, Alena Bartakova1, Carley Haft1, David D. Schlaepfer1, Dwayne G. Stupack1
1Department of Reproductive Medicine, UCSD Moores Cancer Center, La Jolla, CA, USA
Dwayne G. Stupack, e-mail: [email protected]
Keywords: ovarian cancer, autophagy, combination therapy, adverse events, necramed
Received: June 16, 2015 Accepted: September 10, 2015 Published: September 22, 2015
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.
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