Hitting Cancer Targets Hard and Fast: high-dose pulse therapy

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Hitting Cancer Targets Hard and Fast 1/12/2009 To date, all approved tyrosine kinase inhibitors have prolonged half-lives in patients because of the widespread assumption that clinical efficacy will require continuous target inhibition. However, researchers at the University of California San Francisco recently reported that transient, potent kinase inhibition can be as effective as prolonged inhibition for the treatment of CML.
These results suggest that cancer cells are often so addicted to oncogenic signals that even short-term withdrawal is toxic.
Dasatinib effective against CML cells
The study involved the use of dasatinib, a second-generation ABL kinase inhibitor with greater on target potency than imatinib, but with a much shorter serum half-life (3hr vs. 18hr, respectively). The researchers found that cultured human CML cells exposed to dasatinib for as little as 20 minutes followed by drug washout were dead by 48hr. The degree of tumor cell killing was unchanged if the same cells were subjected to 48hr of continuous kinase inhibitor.
The researchers confirmed these findings in chronic-phase CML patients (n=21) enrolled in a phase 1 clinical trial of once-daily dasatinib. They found that inhibition of BCR-ABL kinase activity is transient in these patients, but that efficacy correlates with the degree rather than duration of ABL inhibition.
These results argue that high-dose pulse therapy should be evaluated in early phase clinical trials of targeted agents and may represent one strategy to reduce the toxicity and drug resistance associated with continuous therapy.
Source: Shah NP, Kasap C, Weiser C, et al. Transient potent BCR-ABL inhibition is sufficient to commit chronic myeloid leukemia cells. Cancer Cell. 2008;14:485-493.