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Combination drug therapies targeting at least two different pathways may be the key to making several types of cancer more manageable in the future, according to the findings of a recent analysis. 

“This will be the main avenue for research into cancer treatment, I think, for the next decade and beyond,” predicted investigator Martin Nowak, a professor of mathematics and of biology at Harvard University, Boston, Massachusetts. As the director of the school’s Program for Evolutionary Dynamics, Nowak studies the evolution of drug resistance in cancer. His comments appeared in a statement issued by Harvard University to describe his group’s latest research findings. 

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As Nowak and coauthors wrote in a letter published in the journal Nature (2012;486:537-540), previous studies of targeted therapeutic agents for cancer have shown that most lesions recur at approximately the same time following treatment. Now, the research team’s own results suggest that of the billions of cancer cells that exist in a patient, only about one in a million is resistant to drugs using targeted therapy. Nonresistant cells are destroyed when treatment starts, but the few resistant cells quickly repopulate, and treatment eventually fails, usually within a few months. 

Specifically, Nowak and colleagues analyzed data from patients with chemorefractory metastatic colorectal carcinoma who had been involved in one of two studies of the targeted agent panitumumab (Vectibix). Panitumumab is an inhibitor of epidermal growth factor receptor (EGFR), a protein that can facilitate the growth and division of cancer cells. Twenty-four of the patients had tumors that were initially KRAS wild type; colorectal tumors that are wild type for KRAS are often sensitive to EGFR blockade.

Nine of the patients (38%) whose tumors were initially KRAS wild type developed detectable mutations to the gene, generally within 5 to 6 months following panitumumab monotherapy. Mathematical models indicated that the mutations were present before therapy was initiated, suggesting that the emergence of KRAS mutations is a mediator of acquired resistance to EGFR blockade, and that these mutations can be detected in a noninvasive manner. “They explain why solid tumors develop resistance to targeted therapies in a highly reproducible fashion,” concluded the study authors.

The good news, say Nowak and associates, is that only a small number of genes can confer resistance in colorectal cancer, giving scientists hope that combining panitumumab with other drugs might circumvent resistance. Although the investigators see drug resistance as inevitable in a large metastatic colorectal lesion, remissions can be made to last longer than 5 to 6 months if combination therapies targeting at least two different pathways are used. 

Nowak likens the situation to the rapid evolution of drug resistance in human immunodeficiency virus (HIV), and the subsequent development of the multidrug “cocktail” many HIV-positive patients use to manage their disease. The challenge in the near term, explains Nowak, is to develop the hundreds of drugs that could be needed to address all the possible treatment variations. Once available, however, the multidrug approach not only offers a new avenue for cancer treatment, but may revolutionize such treatment altogether. ONA