title: Principles and current strategies for targeting autophagy for cancer treatment.
abstract: Autophagy is an evolutionarily conserved, intracellular self-defense mechanism in which organelles and proteins are sequestered into autophagic vesicles that are subsequently degraded through fusion with lysosomes. Cells, thereby, prevent the toxic accumulation of damaged or unnecessary components, but also recycle these components to sustain metabolic homoeostasis. Heightened autophagy is a mechanism of resistance for cancer cells faced with metabolic and therapeutic stress, revealing opportunities for exploitation as a therapeutic target in cancer. We summarize recent developments in the field of autophagy and cancer and build upon the results presented at the Cancer Therapy Evaluation Program (CTEP) Early Drug Development meeting in March 2010. Herein, we describe our current understanding of the core components of the autophagy machinery and the functional relevance of autophagy within the tumor microenvironment, and we outline how this knowledge has informed preclinical investigations combining the autophagy inhibitor hydroxychloroquine (HCQ) with chemotherapy, targeted therapy, and immunotherapy. Finally, we describe ongoing clinical trials involving HCQ as a first generation autophagy inhibitor, as well as strategies for the development of novel, more potent, and specific inhibitors of autophagy.
authors.affiliation: Abramson Cancer Center and Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. Ravi.Amaravadi@uphs.upenn.edu
authors.forename: Ravi K
authors.initials: RK
authors.lastname: Amaravadi
authors.forename: Jennifer
authors.initials: J
authors.lastname: Lippincott-Schwartz
authors.forename: Xiao-Ming
authors.initials: XM
authors.lastname: Yin
authors.forename: William A
authors.initials: WA
authors.lastname: Weiss
authors.forename: Naoko
authors.initials: N
authors.lastname: Takebe
authors.forename: William
authors.initials: W
authors.lastname: Timmer
authors.forename: Robert S
authors.initials: RS
authors.lastname: DiPaola
authors.forename: Michael T
authors.initials: MT
authors.lastname: Lotze
authors.forename: Eileen
authors.initials: E
authors.lastname: White
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001343:Autophagy / Q000187:drug effects*; D017326:Clinical Trials, Phase III as Topic; D003131:Combined Modality Therapy; D022162:Cytoplasmic Vesicles / Q000378:metabolism; D006801:Humans; D006886:Hydroxychloroquine / Q000627:therapeutic use*; D007108:Immune Tolerance; D007167:Immunotherapy; D007249:Inflammation / Q000473:pathology; D053858:Metabolic Networks and Pathways / Q000187:drug effects; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000276:immunology / Q000473:pathology* / Q000628:therapy; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D006886:Hydroxychloroquine; D046988:Proteasome Endopeptidase Complex