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  • Review Article
  • Published:

Molecular targets for cancer chemoprevention

Nature Reviews Drug Discovery volume 8, pages 213–225 (2009)Cite this article

Key Points

  • Clinical molecularly targeted chemoprevention has surged forward since the late 1990s, with several targeted agents that prevent cancers, intraepithelial neoplasias and/or microbial infections that lead to carcinogenesis. In addition to vaccines against hepatitis B and human papillomavirus (to prevent cancers of the liver and cervix, respectively), molecularly targeted agents are feasible and effective in preventing breast cancer (selective oestrogen receptor modulators), colorectal adenomas (celecoxib) and prostate cancer (finasteride).

  • Completed chemoprevention trials have encountered several difficulties that pose challenges to the design and conduct of future chemoprevention trials, and hinder translation of their findings into clinical practice. These challenges may be overcome by continuing advances in molecularly targeted prevention approaches.

  • Identification of individuals at high risk of developing cancer (based on models integrating clinical, demographic and molecular data) will assist in selecting optimal populations for chemoprevention trials.

  • Validation of molecular markers that could serve as intermediate surrogate end points for cancer could potentially shorten the length of definitive chemoprevention trials.

  • Development of active molecularly targeted agents (alone or in combination) for chemoprevention should be based on preclinical models, regardless of the efficacy of the drugs in advanced disease. On the other hand, positive results in advanced cancer trials should stimulate prompt evaluation of the agent in the preventive setting as well.

  • Identification of molecular markers that will predict drug sensitivity and/or adverse events will help optimize the risk/benefit ratio of molecularly targeted drugs.

  • Molecularly targeted strategies developed in both premalignant and advanced disease will ultimately streamline cancer prevention research.

Abstract

Vaccines targeting infections with hepatitis B virus, a risk factor for hepatocellular cancer, and human papillomavirus, a risk factor for cervical cancer, are considered major clinical cancer chemoprevention successes. Molecularly targeted agents can prevent breast cancer (raloxifene and tamoxifen), colorectal adenomas (celecoxib), and prostate cancer (finasteride). Nevertheless, the broad translation of chemoprevention to the clinic is not yet a reality. Continuing research of molecular targets promises to expand the reach of chemoprevention and to personalize it as well.

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Figure 1: Schematic for the Erlotinib Prevention of Oral Cancer trial.
Figure 2: Regulation of the hypoxia-inducible factor pathway by hypoxic and non-hypoxic mechanisms and its role in inherited cancer syndromes.
Figure 3: Bridging the gap between cancer treatment and prevention.

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Authors and Affiliations

  1. Department of Thoracic/Head and Neck Medical Oncology The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, 77030, Texas, USA

    William N. William Jr, John V. Heymach, Edward S. Kim & Scott M. Lippman

  2. Department of Cancer Biology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, 77030, Texas, USA

    John V. Heymach

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  1. William N. William Jr
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Correspondence to Scott M. Lippman.

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John V. Heymach, Edward S. Kim and Scott M. Lippman have served on the advisory board of Genentech and OSI.

Related links

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DATABASES

OMIM

Barrett's oesophagus

breast cancer

colon cancer

FAP

gastric cancer

hereditary leiomyomatosis

Kaposi's sarcoma

lung cancer

prostate cancer

von Hippel–Lindau

Glossary

Carcinogenesis

The process of molecular, physiological and histological changes by which normal cells are transformed into cancerous cells.

Intraepithelial neoplasia

(IEN). Lesions confined to the most superficial layer of an organ cavity and/or surface (that is, the epithelial layer). IENs are frequently precursors to invasive cancer.

Epigenetic alterations

Stable gene expression pattern changes that are transmitted from parent to daughter cells, largely irreversible, and different from genetic expression patterns. Epigenetic phenomena are important in determining cellular physiology and pathology. Examples of epigenetic changes are DNA methylation and acetylation.

Angiogenesis

The growth of new blood vessels.

Cyclooxygenase 2

(COX2). The enzyme that is responsible for the synthesis of prostanoids (that is, prostaglandins, prostacyclin and thromboxane) from the precursor arachidonic acid, and that thus has a major role in inflammation. COX2 is generally upregulated during inflammation, whereas its counterpart, COX1, is constitutively expressed in most normal tissues.

Selective oestrogen receptor modulators

(SERMs). A class of drugs that can function as agonists or antagonists of the oestrogen receptor, depending on the tissue type.

Molecular targets

Molecules involved in the development of intraepithelial neoplasia and/or cancer that can (or potentially can) be targeted by pharmacological agents designed to prevent or treat cancer. Examples include tyrosine kinase receptors (including epidermal growth factor, insulin-like growth factor 1, platelet-derived growth factor), other receptors (for example, oestrogen), enzymes (for example, cyclooxygenase 2 and 5α-reductase) and other proteins (for example, vascular endothelial growth factor).

Personalized cancer prevention

The selection of preventive medicine for a patient who is at high risk of cancer, is most likely to benefit from the selected agent or agent combination, and least likely to experience adverse effects of the intervention.

Single nucleotide polymorphism

Variation of a single nucleotide in the DNA sequence, leading to a difference between paired chromosomes in an individual.

Loss of heterozygosity

(LOH). Loss of the normal function of one allele of a gene, when the other allele is already inactivated. In carcinogenesis, LOH frequently occurs in tumour suppressor genes, leading to an interruption of the function of that gene and an increased risk for cancer development.

Phase III trial

Randomized, controlled clinical study, generally conducted on large groups of patients, designed to definitively evaluate the efficacy of a given therapeutic strategy.

Familial adenomatous polyposis

A rare inherited disease associated with a mutation in the APC gene that is clinically characterized by numerous polyps in the colon. If untreated, transformation of the polyps into colon cancer is inevitable.

Surrogate end point

A measure of the effect of a treatment (for example, an increase in the expression levels of a certain protein) that may correlate with a real clinical end point (for example, cancer development).

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William, W., Heymach, J., Kim, E. et al. Molecular targets for cancer chemoprevention. Nat Rev Drug Discov 8, 213–225 (2009). https://doi.org/10.1038/nrd2663

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