Highlights of This Issue

Abstract

Stat5a/b is critical in pathogenesis of prostate cancer and myeloproliferative disorders but only a few pharmacological Stat5a/b inhibitors are currently available. Here, Liao and colleagues identified a new Stat5a/b inhibitor, IST5-002, through structure-based in silico screening and medicinal chemistry by targeting the SH2 domain. IST5-002 blocked both Jak2 and Bcr-Abl–mediated phosphorylation of Stat5a/b and disrupted dimerization, nuclear translocation, DNA binding, and transcriptional activity. IST5-002 potently reduced the expression of Stat5a/b-regulated genes and induced extensive apoptotic cell death in multiple models of prostate cancer and chronic myeloid leukemia. IST5-002 provides a lead structure for further clinical development targeting Stat5a/b-driven solid tumors and hematological malignancies.Notch inhibitors are being tested in the clinic as a therapeutic for multiple cancer indications, but in most cases gastrointestinal toxicities have limited their effectiveness. Proia and colleagues designed a monoclonal antibody, 23814, against the Notch1 ligand-binding domain that cross-reacts with human and mouse Notch1. The antibody blocked Notch1 function in vivo, and inhibited tumor growth without causing gastrointestinal toxicity. The lack of toxicity enabled combination treatment of 23814 with the VEGFR inhibitor tivozanib, which significantly inhibited the growth of several VEGFR inhibitor-resistant tumor models. These results suggest specific Notch1 antibodies may be combined with other angiogenesis inhibitors for the treatment of VEGF inhibitor–resistant tumors.TM4SF1 is highly expressed by both tumor cells and the tumor vascular endothelium, and it internalizes from the cell surface, making it an attractive dual-action target for antibody–drug conjugate therapy. Here, Visintin and colleagues show that an anti-human TM4SF1 antibody conjugated to the auristatin mc-3377 effectively inhibited the growth of human tumor xenografts, and an anti-mouse TM4SF1 antibody targeting the mouse tumor vasculature was similarly effective. When combined, tumor regression was even more pronounced. These data validate TM4SF1 as a suitable therapeutic target to selectively deliver cytotoxic drugs to both tumor cells and tumor vasculature.The Melanoma Dream Team, funded by Stand Up To Cancer and the Melanoma Research Alliance, was formed to examine whether therapy selection based on systematic integration of large-scale genomic and pharmacopeia information improves upon the practice of using a physician's empiric choice for treatment of non–V600E BRAF-mutated metastatic melanoma. LoRusso and colleagues describe a nontreatment pilot study demonstrating the feasibility of using next-generation sequencing techniques to identify molecular aberrations and generate an individualized treatment plan in this patient population. The experience gained in the conduct of this pilot trial led directly to the design of a randomized, statistically driven clinical trial.