Highlights of This Issue

Abstract

The authors evaluated the safety and tolerability of the antisemaphorin 4D antibody VX15/2503 in a first-in-human study. Treatment-related adverse events were primarily Grade 1 or 2; one patient (15 mg/kg) experienced a Grade 3 DLT. No MTD was determined. Complete cellular SEMA4D saturation was generally observed at serum antibody concentrations ≥0.3 μg/mL, resulting in decreased ligand expression. One patient (20 mg/kg) experienced a PR and 27 patients exhibited SD for ≥8 weeks; subjects with elevated B/T lymphocytes exhibited longer progression-free survival. Preclinical studies suggest that combining VX15/2503 with immune modulating agents may improve the clinical activity of checkpoint blockade inhibitors.Triple-negative breast cancers (TNBCs) were reported in population-based studies to be more aggressive with a higher 5-year mortality than non-TNBCs. Podo and colleagues compared phenotype features and survival rates of invasive TNBCs versus non-TNBCs detected during the Italian 18-center HIBCRIT-1 study on screening of asymptomatic women at high genetic-familial risk for breast cancer. Combining an annual screening including magnetic resonance imaging with adequate treatment options, the 5-year overall survival (86% versus 93%) and disease-free survival (77% versus 76%, respectively) were not significantly different, thus showing the possibility of reducing the gap in outcome between TNBCs and non-TNBCs in high-risk women.There is a vital need for effective targeted therapeutics for triple-negative breast cancer (TNBC) patients, yet treatment strategies are challenged by the substantial intertumoral heterogeneity within TNBC. The receptor tyrosine kinase MET is highly expressed in several TNBC subtypes and is a promising therapeutic target. Using the tyrosine kinase inhibitor cabozantinib (XL184), Sameni and colleagues demonstrated that cabozantinib significantly inhibited TNBC growth and invasion in 3D in vitro models and in vivo, yet was ineffective against METneg TNBC cells. These results demonstrate that cabozantinib inhibition may be an effective treatment strategy for TNBC patients.RhoA, the founding member of the Rho GTPase family, is mutated in a large proportion of human diffuse gastric cancers (DGC). To explore the clinical significance, Yoon and colleagues examined RhoA activity in DGC cells, xenografts, and human tumors. RhoA was found to maintain DGC stem-like cells, promote epithelial to mesenchymal transition and chemotherapy resistance, and correlate with poor overall survival in DGC patients. Chemotherapy resistance could be overcome with RhoA inhibition, and thus RhoA is a promising new target in DGC.