The Era of Targeted Therapies
Am Fam Physician. 2008 Feb 1;77(3):294-296.
Cancer has long been recognized as a disease process in which cells invade surrounding tissues and metastasize to distant sites. Multiple genetic and epigenetic mistakes occur as cells become cancerous, and some of these mistakes lead to the expression of proteins that aid in cell survival, invasion, or metastasis.1,2 Our increased understanding of some of these changes has led to the development of the targeted therapies described in the article by Dr. Gerber in this issue of American Family Physician.3
The hope is that targeted therapies will kill cancerous cells without harming normal cells. The effectiveness of this approach depends on the nature of the target and the success in developing an agent that affects only the identified target. Some targets (e.g., breakpoint cluster region-Abelson [BCR-ABL] in patients with chronic myelogenous leukemia) are unique to cancer cells.4 Others (e.g., epidermal growth factor receptor, cluster of differentiation 20) are expressed at higher levels in patients with certain types of cancer, yet they are also expressed on some normal cells, thereby contributing to toxicity.5,6 Even when a target is unique to cancer cells, non-specific effects can occur if the targeting agent affects other proteins. This occurs in patients taking imatinib (Gleevec), a drug that not only inhibits the kinase activity of BCR-ABL, but also inhibits the kinase activity of c-KIT receptors and platelet-derived growth factor receptor (PDGFR).4 Cells that express c-KIT include hematopoietic stem cells and interstitial cells of Cajal; therefore, inhibition of c-KIT by imatinib probably contributes to the myelosuppression and diarrhea that often occur in patients receiving this treatment. Similarly, inhibition of PDGFR in muscle cells most likely contributes to the musculoskeletal pain that often occurs with imatinib treatment.7 The toxicities associated with targeted therapies are generally less severe when the target is not widely expressed in normal cells and when the agent affects only the identified target. Although cross-reactivity contributes to toxicity, it can also extend the clinical use of targeted treatments, as illustrated by the clinical responses that occur when gastrointestinal stromal tumors that overexpress c-KIT are treated with imatinib.7
Most of the targeted therapies that have recently reached the market are very expensive, even when production costs are not high. Drugs that target specific tumor types have relatively small markets, which contributes to their cost.8 Thus, economic barriers could restrict development of lifesaving therapies unless new economic models are developed.
The successes that have occurred using targeted therapies have not been perfect, yet they provide evidence that knowledge about the biology of specific cancers can be used to develop more effective, less toxic treatments. Ideally, nontoxic targeted therapies should be used to eliminate premalignant cells before they become fully cancerous. This would subvert the problems that arise when cancer cells invade surrounding tissues and metastasize to distant sites. Furthermore, premalignant cells have fewer mutations than cancerous cells and are therefore less likely to escape destruction by the targeting agents. As new screening methods become available to allow detection of precancerous lesions, primary care physicians are likely to be instrumental in ensuring that patients are appropriately screened and treated. They also might take a more active role in managing patients with cancer who are receiving targeted therapies. Treatment approaches under development include those that target not only proteins that are critical for tumor cell survival, but also proteins that play a role in cell invasion and metastasis. Thus, the successes with targeted therapies described by Dr. Gerber3 are likely to accelerate as mechanistic insights guide the development of more effective, less toxic treatments for cancer.
Address correspondence to Margaret Offermann, MD, PhD, at Margaret.Offermann@cancer.org. Reprints are not available from the author.
Author disclosure: Nothing to disclose.
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