Targeting cancer metabolism through synthetic lethality-based combinatorial treatment strategies

Curr Opin Oncol. 2018 Sep;30(5):338-344. doi: 10.1097/CCO.0000000000000467.

Abstract

Purpose of review: Targeting cancer metabolism for therapy has received much attention over the last decade with various small molecule inhibitors entering clinical trials. The present review highlights the latest strategies to target glucose and glutamine metabolism for cancer therapy with a particular emphasis on novel combinatorial treatment approaches.

Recent findings: Inhibitors of glucose, lactate, and glutamine transport and the ensuing metabolism are in preclinical to clinical trial stages of investigation. Recent advances in our understanding of cell-intrinsic and cell-extrinsic factors that dictate dependence on these targets have informed the development of rational, synthetic lethality-based strategies to exploit these metabolic vulnerabilities.

Summary: Cancer cells exhibit a number of metabolic alterations with functional consequences beyond that of sustaining cellular energetics and biosynthesis. Elucidating context-specific metabolic dependencies and their connections to oncogenic signaling and epigenetic programs in tumor cells represents a promising approach to identify new metabolic drug targets for cancer therapy.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Amino Acid Transport System ASC / antagonists & inhibitors
  • Amino Acid Transport System ASC / metabolism
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Clinical Trials, Phase I as Topic
  • Glucose / metabolism
  • Glucose Transport Proteins, Facilitative / antagonists & inhibitors
  • Glucose Transport Proteins, Facilitative / metabolism
  • Glutaminase / antagonists & inhibitors
  • Glutaminase / metabolism
  • Glutamine / metabolism
  • Humans
  • Lactic Acid / metabolism
  • Minor Histocompatibility Antigens / metabolism
  • Molecular Targeted Therapy
  • Monocarboxylic Acid Transporters / antagonists & inhibitors
  • Monocarboxylic Acid Transporters / metabolism
  • Neoplasms / drug therapy*
  • Neoplasms / metabolism*
  • Pyruvate Dehydrogenase Complex / antagonists & inhibitors
  • Pyruvate Dehydrogenase Complex / metabolism

Substances

  • Amino Acid Transport System ASC
  • Glucose Transport Proteins, Facilitative
  • Minor Histocompatibility Antigens
  • Monocarboxylic Acid Transporters
  • Pyruvate Dehydrogenase Complex
  • SLC1A5 protein, human
  • Glutamine
  • Lactic Acid
  • GLS protein, human
  • Glutaminase
  • Glucose