Highlights of This Issue

Abstract

Early identification of complex disease-, gene-, and drug-drug interactions and quantitative prediction of their impacts are of great importance to the rational development and optimal use of anticancer drugs. Li and colleagues illustrated the utility of in vitro-in vivo extrapolation and physiologically based pharmacokinetic modeling approach to assess interactions of veliparib, a potential chemosensitizer, with metabolizing enzyme (CYP2D6) and transporter (OCT2) in disease settings (renal impairment). The obtained quantitative information is useful in aiding decision-making regarding whether further clinical studies are needed to assess interactions and risks, and also in guiding dose optimization in response to complex drug interaction scenarios.Aminobisphosphonates (aBPs), such as zoledronate, prevent skeletal-related events in patients with multiple myeloma. However, the extended use of aBPs is associated with osteonecrosis of the jaw as a possible consequence of aBP oversuppression of bone-remodeling. Patel and colleagues studied urinary levels of NTX, a marker of bone resorption, in multiple myeloma patients whose disease was in remission. The authors found that NTX levels remained stable in the 6 months following cessation of aBPs in 28 of 29 patients. This study suggests that less frequent dosing of aBPs is feasible and may help minimize the risks of continued treatment with aBPs while maintaining its benefit.Chemotherapy for gastric cancer is often initially effective but resistance develops quickly. Yoon and colleagues examined a subset of CD44(+) gastric cancer cells with cancer stem cell properties including chemotherapy resistance and found the Hedgehog signaling pathway to be upregulated in these cells. Inhibition of the Hedgehog signaling pathway in these CD44(+) cells reversed chemotherapy resistance in vitro and in vivo. In a randomized clinical trial of chemotherapy with or without the Hedgehog inhibitor vismodegib for advanced gastric cancers, patients with high CD44 expressing tumors treated with chemotherapy plus vismodegib had improved outcomes.The FGFR gene rearrangements were identified in diverse cancers. To explore their prevalence and clinicopathologic characteristics in non-small cell lung cancers (NSCLCs), Wang and colleagues analyzed 1328 NSCLCs for FGFR1, FGFR2, and FGFR3 fusions using RT-PCR and described the clinicopathologic characteristics of patients with FGFR fusions. FGFR1/3 fusions occurred in 1.3% of patients with NSCLCs. FGFR fusions identified a distinct subset of NSCLC with a higher prevalence among smokers with squamous cell carcinoma and relative larger tumor (> 3cm). FGFR is a druggable target and patients with FGFR fusions may benefit from FGFR targeted therapy which needs further clinical investigation.