title: Autophagy modulation: a target for cancer treatment development.
abstract: OBJECTIVE
  Regulation of cellular death is a complex method to maintain cellular homeostasis by protecting against oncogenic development and by recycling damaged cellular debris. Dysregulation of autophagy cellular death is common among a wide range of cancers and presents challenges to current treatment options. This review will evaluate current methods to directly and indirectly modulate autophagy to prevent cancer and to overcome resistance to anticancer therapy.
  
  
  METHODS
  PubMed was searched for keywords: autophagy, hydroxychloroquine, chloroquine, and cell death for preclinical and clinical studies evaluating autophagy-modulating pathways and compounds. Clinicaltrials.gov was searched for keywords: autophagy, hydroxychloroquine, and chloroquine for clinical trials involving autophagy.
  
  
  RESULTS
  The pathways of autophagy are highly prevalent in numerous cancers cell types including leukemia, renal cell cancer, non-small cell lung cancer, melanoma, and advanced solid tumor. Autophagy-inducing compounds represent various drug classes and include everolimus, bortezomib, vorinostat, and arsenic trioxide. The autophagy-inhibiting compounds include chloroquine, hydroxychloroquine, and bafilomycin. Clinicaltrials.gov search identified 32 currently ongoing clinical studies evaluating autophagy and included 14 and 3 studies involving hydroxychloroquine and chloroquine, respectively. These phase I and phase II studies, evaluating the therapeutic benefit of combining autophagy modulators with current anticancer treatments, demonstrate early evidence for application in resistant cancer therapy. Despite positive results, there remains a need to identify direct-acting autophagy inhibitors and for larger phase III trials to be conducted.
  
  
  CONCLUSIONS
  The preclinical evidence for modulating autophagy describes a promising, novel mechanism for enhancing anticancer treatments and overcoming current challenges such as chemotherapy resistance.
authors.affiliation: Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Pharmacy, Baltimore, MD, 21201, USA, aduffy@rx.umaryland.edu.
authors.forename: Alison
authors.initials: A
authors.lastname: Duffy
authors.forename: Jackson
authors.initials: J
authors.lastname: Le
authors.forename: Edward
authors.initials: E
authors.lastname: Sausville
authors.forename: Ashkan
authors.initials: A
authors.lastname: Emadi
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects*; D002986:Clinical Trials as Topic; D015195:Drug Design; D019008:Drug Resistance, Neoplasm; D006801:Humans; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents