The development and testing of a new anti-cancer drug that may overcome side effects of current therapies is described in a study published online this week in Nature Medicine. The work may also help to expand the therapeutic window of drugs that target pro-survival mechanisms of cancer cells.
Inhibition of pro-survival proteins of the BCL family is a promising anti-cancer strategy; however, similarities between family members make the development of specific agents difficult. Drug design strategies currently aim to target BCL-2, an important pro-survival factor frequently elevated in many cancer types. But as the lead compound in clinical testing also inhibits BCL-Xl, which is a related factor required for the survival of platelets, thrombocytopenia - a decrease of platelets in blood - is a limiting adverse effect in treated patients.
Adrew Souers and colleagues modified existing anti-BCL drugs to generate a more BCL-2 specific compound that has less affinity for BCL-XL, and thus reduced platelet toxicity. They report that the compound is effective in several tumor models in vivo and displays reduced adverse effects in three patients with refractory leukemia, showing a promising activity and safety profile which may in the future refine and improve the application of pro-apoptotic therapy in cancer.
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