Highlights of This Issue

Abstract

Voss and colleagues present the largest cohort of RCC outlier cases with long-term response to mTOR inhibitors reported to date. They perform whole-exome and targeted massive parallel sequencing analysis for biomarker discovery and provide functional validation, proposing two rational candidates, mTOR and TSC1. This could be relevant beyond the field of kidney cancer becauses rapalogs are now approved for the treatment of PNET, breast cancer, SEGAs and angiomyolipomas. The authors' investigation of tumor heterogeneity gives further support to the principle of targeting “trunk mutations” and suggests that functional convergent evolution of pathways like “braided river” can sensitize tumors to single-agent targeted therapy.Although combination of bendamustine with rituximab (BR) shows clinical activity against relapsed/refractory diffuse large B-cell lymphoma (DLBCL), the standard therapy has not been fully established. Kaneko and colleagues demonstrated that YM155, a survivin suppressant, synergistically enhanced the antitumor activity of bendamustine through the inhibition of bendamustine-induced activation of the ATM pathway and accumulation of survivin at the G2/M phase. Further, triple combination of YM155 with BR significantly prolonged overall survival as compared with BR in a disseminated activated B-cell-like DLBCL model, suggesting the potential of the triple combination as a new combination therapy to treat relapsed/refractory DLBCL.EphA2 is considered an important therapeutic target because it is involved in many processes crucial to malignant progression. Among the various therapeutic strategies targeting EphA2, dasatinib is the farthest along with regard to clinical development. However, reliable predictors of response and the mechanisms relevant to dasatinib response have been largely lacking. Huang and colleagues have identified that CAV-1, EphA2 phosphorylation at S897 and the status of PTEN are key determinants of dasatinib response. Moreover, they discovered a previously unknown mechanism involving the association between CAV-1, EphA2 and the heterodimer BRAF/CRAF, which has significant implications for designing new therapeutic combinations and ongoing dasatinib-based clinical trials.Nonmuscle invasive bladder cancer, characterized by a high rate of recurrence, is a high-cost disease in cancer management. Given their stable, reliable, and early appearance, Su and colleagues analyzed DNA methylation changes in urine sediments serially collected from individual TURBT patients at the time of follow-up visits. The incorporation of both hyper- and hypo-DNA methylation profiles showed the ability of functional markers SOX1, L1-MET, and IRAK3 to predict tumor recurrence with high sensitivity and specificity and highlighted the translational implications of their use in longitudinally personalized monitoring of bladder tumor recurrence in a noninvasive manner.