Topic: NCI Provocative Questions

What is the molecular mechanism by which a drug (such as aspirin or metformin) that is chronically used for other indications protects against cancer incidence and mortality?

Background: Numerous observational studies indicate that some drugs commonly used to treat or prevent diseases other than cancer reduce the risk of developing some cancers or produce a better cancer prognosis. For example, a recently published meta-analysis shows that people taking low-dose aspirin to reduce risk of vascular disease have a 20 to 30% lower risk of death due to several types of cancer, including cancers of the esophagus, lung, and pancreas, as well as colon. Other commonly used drugs, such as metformin used for the treatment of Type 2 diabetes, are also associated with a lower risk of cancer. However, the mechanisms by which these agents affect cancer risk and outcome are not well understood, and research needs to move beyond observational studies. Successful applications will determine which changes induced by drugs that are used commonly and chronically for other diseases are key for cancer prevention. The drugs chosen for study should already show good preventative effects in previous studies.

Feasibility: Clinical data sets describing the consequences of long-term use of FDA-approved drugs could be mined for the association of drugs with incidence of various cancer types, while ruling out the possibility of a confounding interaction with the disease being treated. For those drugs already identified as being associated with a reduced risk of cancer, the mechanism(s) by which they reduce this risk remain to be identified. In the case of aspirin, for example, most speculation on the mechanism of action has centered on changes in its anti-inflammatory activity. Since inflammation associated with cancer development is well studied, it might be possible to establish a causal link to changes in inflammation. For metformin use, the link to cancer prevention has been suggested for patients with Type 2 diabetes. If we can determine why this occurs, we may be able to learn how and why non-diabetics will respond. Researchers should seek to move beyond correlative studies and establish careful mechanistic studies that link drug action to changes that alter cancer incidence.

Implications of success: Elucidating the key molecular mechanisms by which these agents work would be a major breakthrough in cancer prevention. Understanding which cellular events can be regulated to change the risk of cancer development would identify clear biochemical and physiological events whose regulation controls some aspects of cancer prevention. This work could also provide molecular pathways that harbor other targets for prevention and encourage the development of second-generation drugs that might diminish toxicities associated with current agents while maintaining efficacy. Success in these studies would provide models for the types of responses that mark good chemoprevention trials.

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