Highlights of This Issue

Abstract

Malignant peripheral nerve sheath tumors (MPNST) are therapy-resistant aggressive sarcomas that are frequently found in patients with neurofibromatosis. Using a combined gene expression database of mouse and human neurofibromas and MPNSTs and a Bayesian factor regression model analysis driven by a Ras-induced gene expression signature, Patel and colleagues identified overexpression and amplification of Aurora kinases in MPNSTs. The functional significance of Aurora kinase overexpression in MPNST was verified in vitro and in vivo with Aurora kinase short hairpin RNAs and compounds that inhibit Aurora kinase. Thus, transcriptome analyses, coupled with preclinical testing, identified candidates for molecular-targeted therapeutics, and blocking Aurora kinases may be a viable treatment platform for MPNST.Despite new therapeutics being tried in the clinic, multiple myeloma still remains incurable. To explore oncolytic viruses as therapeutic agents for multiple myeloma, Thirukkumaran and colleagues tested reovirus multiple myeloma oncolysis in vitro, ex vivo, and in vivo and observed its effects on human hematopoietic stem cell repopulation/differentiation in a murine model. Reovirus showed significant oncolytic activity as monotherapy against the majority of multiple myeloma cell lines, including bortezomib-resistant cell lines, ex vivo tumor, and in vivo disseminated disease and did not affect the hematopoietic stem cell compartment. This study highlights the potential for reovirus as a novel therapy for multiple myeloma.Aberrant Notch signaling is implicated in breast cancer disease progression. PF-03084014 is a small-molecule γ-secretase inhibitor that blocks pan-Notch signaling. Zhang and colleagues characterized the diverse biologic properties of PF-03084014 and evaluated the biomarkers in a panel of breast xenograft models. PF-03084014 showed significant antitumor efficacy in a subset of tested models through a pleiotropic mechanism. The Notch pathway target gene expressions were correlated with the antitumor efficacy of PF-03084014 and can potentially serve as biomarkers for both proof of mechanism and patient enrichment. This work provides guidance for the clinical investigation of PF-03084014 therapy in breast cancer patients.Paclitaxel-induced sensory peripheral neuropathy can be dose limiting and may affect a patient's quality of life. To identify biomarkers for the prediction of paclitaxel-induced peripheral neuropathy, Baldwin and colleagues performed a genome-wide association study of women receiving single-agent paclitaxel as adjuvant therapy for breast cancer. Several novel genetic loci were associated with the onset and severity of peripheral neuropathy, including a common variant in FGD4, a causal gene for the congenital peripheral neuropathy Charcot-Marie-Tooth disease. These genetic markers show promise as predictors of increased risk of paclitaxel-induced sensory neuropathy and may guide the selection and use of this important chemotherapy drug.