Dr. Amaravadi investigates mechanisms of resistance to cancer therapies. A primary focus of his research is to understand the role of autophagy as a resistance mechanism to chemotherapy and targeted therapy in advanced cancers. These studies began with mouse models of cancer therapy where autophagy was identified as a key mechanism of resistance to chemotherapy, and genetic or chemical blockade of autophagy with chloroquine derviatives augmented the efficacy of chemotherapy. Based on these findings Dr. Amaravadi, working with many other investigators, completed a series of phase I clinical trials involving hydroxychloroquine in combination with cancer therapies for a number of malignancies. These clinical trials represent the first deliberate attempt to modulate autophagy therapeutically and demonstrated the feasibility of this strategy. Ongoing research focuses on phase II efficacy studies of hydroxychloroquine combinations, designing and optimizing more potent novel dimeric chloroquine derivatives as cancer therapeutics, identifying the molecular target of chloroquine derivatives, and understanding how chloroquine derivatives affect other stress response pathways and the tumor microenvironment. A secondary focus is on developing better molecular tools to measure autophagy dynamics that can be applied to clinical samples, and identifying genetic or epigenetic determinants of sensitivity to autophagy inhibitors.