Cancer Research Moves Beyond the Original Hallmarks of Cancer
Strategies Targeting the Hallmarks
Click to enlarge.
This figure illustrates some of the many approaches employed in developing therapeutics targeted to the known and emerging hallmarks of cancer.
EGFR indicates epidermal growth factor receptor; CTLA4, cytotoxic T lymphocyte-associated antigen 4; mAb, monoclonal antibody; HGF, hepatocyte growth factor; VEGF, vascular endothelial growth factor; PARP, poly-(ADP ribose) polymerase.
Source: Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646-674. Reprinted with permission.
Impaired Metabolism: Cancer’s Sweet ToothResearch has shown that cancer cells undergo a metabolic switch, a fundamental change in the metabolism of all four major classes of macromolecules (carbohydrates, proteins, lipids, and nucleic acids).3
The Warburg effect4 is the best characterized metabolic change, in which cancer cells switch their means of energy production from oxidative phosphorylation to glycolysis, even in the presence of normal levels of oxygen (thus termed aerobic glycolysis). To compensate for the reduced ATP production efficiency with aerobic glycolysis, cancer cells increase uptake of glucose, a phenomenon that has proved useful for tumor detection and monitoring, serving as the basis for [18F]fluorodeoxyglucose positron emission tomography (FDGPET). The Warburg effect has since been demonstrated in numerous tumor types, and genes for glycolysis are overexpressed in the majority of cancers examined, leading to the suggestion that altered metabolism should be considered an additional hallmark of cancer.3,5
A variety of therapeutic strategies targeting different points in the glycolytic pathway are being evaluated.3 During the initial stages of tumor growth, the low oxygen environment promotes expression of hypoxiainducible factor (HIF) 1, a major transcription factor that subsequently activates numerous glycolytic enzymes, including pyruvate dehydrogenase kinases (PDKs), lactate dehydrogenase (LDH)6, and glucose-6-phosphate dehydrogenase (G6PD).
A variety of inhibitors targeting these proteins have been developed. The G6PD inhibitor, 6-amino-nicotinamide, has demonstrated antitumor effects in leukemia, glioblastoma, and lung cancer cell lines.3 Salts of dichloroacetate (DCA), which inhibit PDK, are in phase II trials for squamous cell carcinoma of the head and neck.7 EZN-2968 from Enzon Pharmaceuticals (an antisense oligonucleotide inhibitor of HIF1) is in phase I trials for advanced solid tumors.8 LDH inhibitors are among the most promising agents, though they remain in the early stages of development.6 The serine/threonine kinase AKT is also an important driver of the glycolytic phenotype, stimulating ATP generation through multiple mechanisms; the AKT inhibitor MK-2206 (Merck & Co.) is currently undergoing phase II trials in non-small cell lung cancer (NSCLC) and hematological cancers, among others.9