Bringing the Oncology Community Together

Cancer Research Moves Beyond the Original Hallmarks of Cancer

Jane de Lartigue, PhD
Published Online: Wednesday, June 20, 2012

Strategies Targeting the Hallmarks
of Cancer

Strategies Targeting the Hallmarks of Cancer 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.

At the turn of the millennium, Douglas Hanahan and Robert Weinberg presented their seminal article on the “hallmarks of cancer,” six alterations in cellular physiology that are essential to the transformation of normal cells into cancerous ones.1 Just over a decade has passed since then, and though the hallmarks remain central to tumor biology and research, it is now generally accepted that the original six hallmarks may not be sufficient for malignant transformation, and that additional hallmark capabilities may be involved.2

Impaired Metabolism: Cancer’s Sweet Tooth

Research 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

Oxidative phosphorylation

A metabolic pathway that uses energy released by the oxidation of nutrients to produce adenosine triphosphate (ATP).

Aerobic glycolysis

In normal cells, in the absence of oxygen, energy production switches from oxidative phosphorylation to anaerobic glycolysis, whereby glucose is converted into pyruvate in order to generate ATP. Cancer cells use glycolysis to generate energy even in the presence of oxygen.
AMP-activated protein kinase (AMPK) couples energy status to growth signals, and as such, a considerable amount of research has focused on determining whether agonists of AMPK could be used to recouple these signals in cancer cells and shut down cell growth. Examples of AMPK agonists that are under evaluation include the commonly used antidiabetic drugs metformin and phenformin.3

Page: 1234Next Page (2) >>
Related Articles
Next-Generation Targeted Therapies in NSCLC
In this segment, panelists discuss the number of early-phase clinical trials that have demonstrated impressive efficacy for next-generation ALK and EGFR inhibitors for patients with non-small cell lung cancer.
Targeted Therapies Usher in a New Era in CLL: Wierda Discusses Key Facets of Emerging Agents
The approval of the first small-molecule, targeted therapy for patients with chronic lymphocytic leukemia (CLL) launches a new era that promises to transform management of the disease, yet significant challenges in translating research advances into improvements in long-term outcomes remain
The Retreatment Question: Research Suggests Benefits to Continuing Molecularly Targeted Therapy Beyond Progression
The readministration of a cytotoxic antineoplastic agent is a well-established management paradigm in a number of malignancies, yet it is generally believed such a strategy may not prove beneficial if the patient experiences disease progression while receiving the therapy.
Hopes Revived for Targeting the “Undruggable” RAS Family
The members of the RAS oncogene family are central cogs in many different cell-signaling pathways, coordinate a variety of important cellular processes, and are highly mutated in a number of different cancers, including several with extremely poor prognosis.
Most Popular Right Now
More Reading
External Resources

American Journal of Managed Care
Pharmacy Times
Physicians' Education Resource
Physician's Money Digest
Specialty Pharmacy Times
OncLive Resources

OncLive TV
Oncology Nurses
Web Exclusives

About Us
Advisory Board
Contact Us
Forgot Password
Privacy Policy
Terms & Conditions
Intellisphere, LLC
666 Plainsboro Road
Building 300
Plainsboro, NJ 08536
P: 609-716-7777
F: 609-716-4747

Copyright OncLive 2006-2014
Intellisphere, LLC. All Rights Reserved.