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Modeling Reveals Strategy to Delay Drug Resistance

Several recent studies (click here for an example) have used evolutionary theory to predict that the current practice of giving high-dose chemotherapy to treat cancer will in many cases drive tumors to develop drug resistance and that discontinuous dosing is likely to forestall the development of drug resistance and increase the chances of therapeutic success. Now, a multi-institutional study using animal models of human melanoma has generated data supporting these theoretical predictions.

Reporting its work in the journal Nature, a team of investigators led by Darrin Stuart of the Novartis Institutes for Biomedical Research and Martin McMahon of the University of California, San Francisco, demonstrated that continuous dosing of mice with human-derived melanomas with the drug vemurafenib led to drug resistance in 20 percent of the mice after eight weeks. However, the researchers observed that the drug-resistant tumors had actually grown dependent on drug for continued growth, and that cutting of the supply of drug led to regression of established drug-resistant tumors within 10 days of drug withdrawal.

Vemurafenib is used to treat the approximately 60 percent of melanoma patients whose tumors have what’s known as the BRAF V600E mutation. The drug works by turning off the abnormally active BRAF protein produced by this mutation, causing cell death.

These results led the investigators to propose that since continuous dosing inevitably selects for drug-resistant tumor cells, discontinuous dosing could put surviving drug-resistant cells at a disadvantage every time they started to get the upper hand in a tumor. To test this idea, they transplanted human melanoma cells into mice and treated one group continuously with vemurafenib and a second group that received the same amount of drug but on a four weeks on/two weeks off schedule. The mice receiving continuous dosing developed lethal drug-resistant disease within 100 days, but none of the mice treated with discontinuous dose developed drug-resistant disease over 200 days.

This work, which was supported in part by the National Cancer Institute, is detailed in a paper titled, “Modelling vemurafenib resistance in melanoma reveals strategy to forestall drug resistance in melanoma.” ¬†An abstract of this paper is available at the journal's Web site.
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