Highlights of This Issue

Abstract

There exists uncertainty regarding optimal therapy combinations with inhibitors of vascular endothelial growth factor (VEGF) and its receptor (VEGFR). We assessed whether chemotherapy synergizes with VEGF/VEGFR (VEGF/R) inhibitors in a database of 1,498 patients with advanced solid malignancies treated on phase I protocols, 741 with VEGF/R inhibitors. Our analysis identified a synergistic interaction between concomitant chemotherapy and VEGF/R inhibitor use in producing clinical benefit on trial (defined as objective response or stable disease lasting at least 6 months). Specifically, we identified the antimetabolite chemotherapy class to exhibit the highest degree of synergy.Reolysin, the infusible form of reovirus, selectively enters malignant cells and is associated with clinical response when combined with chemotherapy. Sborov and colleagues present the first evidence of its use in hematologic malignancies and showed that the agent was well tolerated and associated with no dose-limiting toxicities in patients with relapsed multiple myeloma. Reovirus selectively entered myeloma cells, but only minimal viral replication and apoptosis was evident, suggesting that viral proliferation is necessary to induce clinically relevant antitumor activity. Further investigation will be necessary to elucidate the mechanisms of viral-mediated antitumor activity and identification of effective combination therapeutic strategies.Activation of the MET/HGF pathway has been associated with a range of tumor biology and has been shown to result in worse outcomes for patients. MET can be stimulated by HGF-dependent mechanisms or by HGF-independent mechanisms such as gene amplification, mutations, or transcriptional upregulation. Liu and colleagues describe the discovery and preclinical characterization of a bivalent MET antibody, LY2875358, which inhibits both HGF-dependent and HGF-independent MET activation but lacks functional agonist activity. The potent antitumor activity described by the authors supports the ongoing clinical evaluation of LY2875358 in patients with MET-activated tumors.AMACR promotes the β-oxidation of branched-chain fatty acids and is frequently overexpressed in common carcinomas, mostly through transactivation. Li and colleagues performed genomic profiling of myxofibrosarcomas and validated amplification of AMACR at 5p13.3 in 20% of myxofibrosarcomas that exhibited mRNA and protein overexpression with negative prognostic impact. In vitro and in vivo functional assays demonstrated that the oncogenic function of AMACR was linked to upregulated cyclin D1 and cyclin T2, hence promoting cell proliferation. Ebselen oxide, a nonsubstrate-based inhibitor of AMACR, enabled selective susceptibility in AMACR-expressing myxofibrosarcomas through induction of cellular apoptosis and proteasome-mediated degradation of AMACR protein.