Highlights of This Issue

Abstract

Next generation sequencing and array CGH analysis of one patient's neuroendocrine prostate cancer revealed a homozygous deletion of the methylthioadenine phosphorylase (MTAP) gene. Concurrently, a patient-derived xenograft model was established. A novel two-drug therapy markedly decreased xenograft growth rate and increased cancer cell apoptosis, without toxicity to the mouse host. Moreover, decreased MTAP expression was strongly associated with poor outcome in prostate cancer. This study suggests a unique therapy for patients with MTAP- deficient cancers, with significant implications for personalized oncology, since MTAP is absent in 10 to 75 % of the most intractable kinds of human cancers.Non-small cell lung cancer (NSCLC) remains one of the most difficult to treat malignancies, and novel therapeutics and patient selection strategies are urgently needed. The uracil-metabolizing enzyme dUTPase is reported to protect tumor cells from aberrant uracil misincorporation into DNA during treatment with thymidylate synthase (TS)-targeted therapies. Wilson and colleagues report that dUTPase is significantly overexpressed in NSCLC cell lines and clinical specimens and show that the silencing of dUTPase expression dramatically sensitizes NSCLC cells to cytotoxicity induced by the TS inhibitors pemetrexed and fluorodeoxyuridine. Targeting dUTPase represents a novel mechanism-based therapeutic approach to significantly enhance the efficacy of TS-targeted chemotherapies.Antibodies that block ligand binding to the type-1 insulin-like growth factor receptor (IGF-1R) have limited clinical antitumor activity. Bid and colleagues examined the effect of the SCH717454 antibody on angiogenesis in vitro and in vivo. Antibody blockade of IGF-1R prevented VEGF-stimulated proliferation of vascular endothelial cells, providing the first direct evidence of the involvement of IGF-1R signaling in angiogenesis. Both in vitro and in a mouse model, IGF-2 circumvented the inhibitory activity of SCH717454. The data yield insight into the mechanism of action and resistance to receptor-targeted antibodies and for improved strategies for targeting the IGF-axis for cancer treatment.To achieve the full potential of single-agent therapies targeting specific signaling proteins, it is essential to explore why drug resistance occurs in the majority of treated patients over time. Chen and colleagues investigated the role of alternative signaling pathways in mediating resistance to lapatinib inhibition of HER2-amplified gastric cancer cells. The data showed that activation of MET receptor in MET-overexpressing cells can overcome HER2 inhibition by restoring common downstream signaling pathways more effectively than the activation of other receptor tyrosine kinases. Thus, this finding suggests MET activation as a potential mechanism of resistance to lapatinib inhibition.