Autophagy Inhibition in Cancer Therapy: Progress and Unanswered Questions

Based on numerous preclinical models which have demonstrated autophagy promotes tumor cell survival and resistance to metabolic and therapeutic stresses, clinical trials involving the autophagy inhibitor hydroxychloroquine have been launched for patients with refractory malignancies. Currently there are nearly 30 early phase clinical trials involving HCQ for a variety of malignancies in development or actively accruing patients in the United States and abroad. The preliminary results of a number of these HCQ clinical trials lead by the University of Pennsylvania will be presented. The development and results of novel pharmacodynamic and pharmacokinetic assays to characterize autophagy inhibition in peripheral blood cells and tumor tissue in these clinical trials will be highlighted. The questions that have been raised by the clinical data that can be answered in the laboratory will be posed.  Finally, our efforts to synthesize a more potent second generation autophagy inhibitor, and the identification of a potential biomarker that predicts sensitivity to autophagy inhibition and can be rapidly translated into a clinical assay will be presented.