Principles and current strategies for targeting autophagy for cancer treatment

Ravi K. Amaravadi, Jennifer Lippincott-Schwartz, Xiao Ming Yin, William A. Weiss, Naoko Takebe, William Timmer, Robert S. DiPaola, Michael T. Lotze, Eileen White

Research output: Contribution to journalReview article

574 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)654-666
Number of pages13
JournalClinical Cancer Research
Volume17
Issue number4
DOIs
StatePublished - Feb 15 2011

    Fingerprint

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Amaravadi, R. K., Lippincott-Schwartz, J., Yin, X. M., Weiss, W. A., Takebe, N., Timmer, W., DiPaola, R. S., Lotze, M. T., & White, E. (2011). Principles and current strategies for targeting autophagy for cancer treatment. Clinical Cancer Research, 17(4), 654-666. https://doi.org/10.1158/1078-0432.CCR-10-2634