Novel Strategies to Discover Effective Drug Targets in Metabolic and Immune Therapy for Glioblastoma

Curr Cancer Drug Targets. 2017;17(1):17-39. doi: 10.2174/1568009616666160512145436.

Abstract

Glioblastoma multiforme is a common primary brain tumor, which exhibits an imbalance between glioma cell growth and glucose metabolism. Recent discoveries have found that the multiple pathways and downstream genes involved in the dysregulated metabolic pathway allow tumor to manifest and progress, which is critical to patients with glioblastoma associated with significant systemic and immunosuppression. Moreover, immune microenvironment is considered a major obstacle to generating an effective antitumor immune response. Therefore, identification of patient-specific tumor antigens through highly personalized approach, and effective combination with other therapeutic modalities such as molecular agents targeting tumor metabolic oncogene addiction and potent host immune modulators, may provide targets for more effective therapeutic strategies for glioblastoma. In this review, we aim to highlight the most recent findings regarding glucose uptake and proliferation, cell mobility and to expand our investigations and more comprehensively examine different aspects of glucose metabolism in glioblastoma, such as pentose phosphate pathway (PPP) and its enzymes, metabolic modulation of genetics and epigenetics and key metabolic regulators, importantly, tumor cell-induced glucose deprivation inhibits T-cell glycolysis and immunogenic functions. Furthermore, this review will concentrate on how to discover effective drug targets to regulate glucose metabolism in tumor and T cell growth for future glioblastoma therapies, and the challenges faced by the field of metabolism in tumor immune microenviroment.

Publication types

  • Review

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Apoptosis Regulatory Proteins
  • Brain Neoplasms / drug therapy
  • Brain Neoplasms / genetics
  • Brain Neoplasms / metabolism*
  • Drug Discovery
  • Epigenesis, Genetic
  • Gene Expression Regulation, Neoplastic
  • Glioblastoma / drug therapy
  • Glioblastoma / genetics
  • Glioblastoma / metabolism*
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Isocitrate Dehydrogenase / genetics
  • Isocitrate Dehydrogenase / metabolism
  • Mechanistic Target of Rapamycin Complex 2
  • Molecular Targeted Therapy / methods
  • Multiprotein Complexes / metabolism
  • Pentose Phosphate Pathway
  • Phosphoric Monoester Hydrolases
  • Pyruvate Kinase / genetics
  • Pyruvate Kinase / metabolism
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism
  • TOR Serine-Threonine Kinases / metabolism

Substances

  • Antineoplastic Agents
  • Apoptosis Regulatory Proteins
  • Intracellular Signaling Peptides and Proteins
  • Multiprotein Complexes
  • Isocitrate Dehydrogenase
  • IDH1 protein, human
  • Pyruvate Kinase
  • Mechanistic Target of Rapamycin Complex 2
  • TOR Serine-Threonine Kinases
  • Phosphoric Monoester Hydrolases
  • TIGAR protein, human