Highlights of This Issue

Abstract

The taxanes paclitaxel and docetaxel are widely used for the treatment of solid tumors. Recently, it was shown that cigarette smoking can influence the metabolism and toxicity profile of some important anticancer drugs. de Graan and colleagues designed a study to assess the influence of smoking on the metabolism and toxicities of taxane therapy. The pharmacokinetics of paclitaxel and docetaxel were not altered by smoking, but interestingly, smokers were found to have less hematologic toxicity during anticancer treatment.Approximately 5% to 10% of gastrointestinal stromal tumors (GIST) have pathogenetic activating mutations of the platelet-derived growth factor receptor (PDGFRA) tyrosine kinase. The most common variant, PDGFRA D842V, is resistant to currently approved tyrosine kinase inhibitors (TKI). Treatment of PDGFRA D842V–mutant GIST with conventional TKIs results in markedly inferior clinical outcomes compared with treatment of KIT-mutant GIST. Heinrich and colleagues identified crenolanib as a potent inhibitor of PDGFRA D842V with an IC50 of approximately 10 nmol/L (making it 100–150 times more potent than imatinib). Based on these results, a phase II study of crenolanib for advanced PDGFRA D842V–mutant GIST has been initiated (NCT01243346).Giant-cell tumor of bone (GCTB) is an aggressive osteolytic tumor characterized by osteoclast-like giant cells and their precursors that express RANK and mononuclear stromal cells that express the ligand RANKL, a key mediator of osteoclast activation. Denosumab binds to RANKL, eliminating giant cells, inhibiting bone destruction, and shifting the bone turnover balance in favor of bone formation. Branstetter and colleagues report that histologic evidence confirms these effects and shows that denosumab-induced interruption of the dysregulated overexpression of RANKL reduces tumor growth and promotes differentiation to normal tissue. This unique biologic mechanism is clinically relevant for GCTB treatment and for future cancer research.Docetaxel is extensively metabolized in the liver, but mechanisms by which the drug is taken up into hepatocytes remain unclear. de Graan and colleagues designed a translational study to investigate the influence of the OATP1B uptake transporters on docetaxel metabolism in transfected cell models, transporter knockout mice, and patients with inherited, reduced-function variants in the genes encoding these transporters. These findings shed new light on factors affecting the elimination of this widely used drug and provide a framework for future investigations aimed at tailoring drug dosage in cancer patients.