Highlights of This Issue

Abstract

Bortezomib is the first proteasome inhibitor approved for the treatment of cancer. The determinants of resistance to bortezomib, however, remain poorly defined. Here, Weniger and colleagues used gene expression profiling to investigate the cellular response to proteasome inhibition in mantle celllymphoma. They found that induction of a strong NRF2-regulated antioxidant response in tumor cells during bortezomib treatment identified patients with superior clinical response. In contrast, high basal antioxidant capacity was associated with a reduced stress response and inferior clinical outcome. These results indicate that high cellular antioxidant capacity contributes to bortezomib resistance and may represent a therapeutic target.Malignant pleural mesothelioma (MPM) is an aggressive tumor that has high resistance to chemotherapy and radiotherapy. Genetic alteration of TP53 is rare in MPM, even though MPM exhibits antiapoptosis and cell cycle alterations suggestive of functional p53 deficiency. The microRNA-34s (miR-34s) are direct transcriptional targets of p53. Here,Kubo and colleagues found that miR-34b/c expression was frequently silenced by DNA methylation in MPM, resulting in loss of tumorsuppressive p53 function. This study provides new insights into the molecular pathogenesis of MPM and suggests that miR-34b/c could be a potential therapeutic target.Preclinical data suggest human Vα24Vβ11 natural killer T cells (NKT) cells, activated by α-galactosylceramide presented by dendritic cells (DC), have antitumor potential. In a phase I clinical trial,Nicol and colleagues evaluated the effects of administration route (intravenous vs. intradermal) and α-galactosylceramide-pulsed DC dose on NKT cell stimulation. They found that both administration route and DC dose had a major impact on NKT cell responses and on secondary immune effects consequent on NKT cell activation. Inflammatory flares involving tumor deposits were frequently observed. These data provide important insights into the design of immunotherapy studies using DC-based NKT cell stimulation.BNC105P is an inhibitor of tubulin polymerization that has vascular disrupting and anti-proliferative effects. In this issue, Rischin and colleagues report on a first-in-human phase I trial of this agent. The experimental design incorporated a number of pharmacokinetic and pharmacodynamic assessments.Dynamic contrast enhanced MRI was used to assess tumor blood flow following exposure to drug, and a novel immunoblot densitometry assay was developed that assessed the level of polymerized tubulin in PBMCs isolated from trial subjects.BNC105P was associated with pharmacodynamic changes consistent with its mechanism of action and had a favorable toxicity profile at the recommended dose level.