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

Area of Science:

• Oncology
• Cell Biology
• Pharmacology

Background:

• Serous ovarian cancers (SOC) often exhibit resistance to programmed cell death mechanisms.
• Understanding alternative cell death pathways is crucial for developing effective cancer therapies.

Purpose of the Study:

• To investigate the sensitivity of programmed death-resistant SOC cells to agents modulating autophagy.
• To identify FDA-approved agents that perturb autophagy in ovarian cancer and evaluate their combinatorial efficacy.

Main Methods:

• A comprehensive screen of FDA-approved agents targeting autophagy in ovarian cancer models.
• In vitro and in vivo experiments assessing cytotoxicity and disease burden.
• Analysis of autophagosome formation and correlation with treatment efficacy.

Main Results:

• Over a dozen FDA-approved agents were identified that perturb autophagy in ovarian cancer.
• Combinatorial drug use targeting distinct autophagy regulators maximized cytotoxic effects.
• A pentadrug combination significantly outperformed dual-drug therapy in vivo, eradicating disease with no systemic toxicity.

Conclusions:

• Autophagy modulation represents a viable therapeutic strategy for SOC, even in cases resistant to conventional cell death pathways.
• Multi-modal targeting of the autophagy pathway shows significant promise for treating recalcitrant serous ovarian cancers.