Highlights of This Issue

Abstract

In an effort to target the tumor vasculature, metronomic approaches to deliver chemotherapy seek to deliver small doses frequently to avoid toxicities of intermittent doses at the maximum tolerated dose (MTD). Pioneered in the laboratory of the late Dr. Judah Folkman, applying this approach to humans has offered promise, but how to achieve the maximal value of this approach in the clinic has remained uncertain. Complementary preclinical papers by Hashimoto and colleagues and Merritt and colleagues offer an important opportunity to apply this strategy in ovarian cancer. An oral formulation of topotecan, an anti-topoisomerase I cytotoxic in combination with pazopanib, a recently approved VEGF-R kinase antagonist, caused striking suppression of ovarian carcinoma xenograft growth. Importantly, the ovarian carcinoma cells in the Merritt paper expressed VEGF-R in the tumor cells. Thus, this metronomic approach when applied to human ovarian cancer could cause beneficial effects in both the tumor and endothelial cell compartment. These findings are “low hanging fruit” for clinical trial development, given the known activity of topotecan as a single agent in MTD doses in ovarian cancer, albeit with toxicity that might be avoidable if combined with pazopanib on a metronomic schedule.In-transit metastatic melanoma typically presents as multifocal lesions, providing a unique setting for evaluating the utility of gene expression profiling in defining patient-tailored regional therapeutic strategies as well as assessing treatment efficacy. Augustine and colleagues evaluated 55 in-transit melanoma lesions across 29 patients and showed that, within a patient, lesions harbor concordant patterns of gene expression. Their results demonstrate that a single in-transit lesion is representative of residual tumor burden in terms of gene expression signatures predictive of response to therapy and can be used to characterize the biology of a patient's in-transit disease.Six members of the peroxiredoxin (PRDX) family of thiol-dependent peroxidases have been identified in mammalian tissues. Among them, PRDX6 has a unique property; it possesses phospholipase A2 (PLA2) activity in addition to peroxidase and, thus, is considered a bifunctional enzyme. However, the physiological role of its PLA2 activity is not determined yet. In this study, Ho and colleagues analyzed functions of PRDX6 in lung cancer cells. This study is the first to define the functions of PRDX6's enzymatic activities in metastasis and to show arachidonic acid's involvement in PRDX6 action in intact cells. These novel findings provide a significant step towards elucidating the role of PRDX6 in cancer and the mechanism of its action.Nutlin-3a is a small molecule MDM2 antagonist that stabilizes p53 by blocking the interaction between p53 and MDM2. Numerous studies have supported the potential clinical use of Nutlin-3a as an anticancer agent, based on the potent ability of Nutlin-3a to promote growth arrest or apoptosis in p53-wild-type cancer cells. In the study by Moran and Maki, it was found that Nutlin-3a treatment caused a cytoskeletal rearrangement in multiple p53 wild-type cancer cell lines. The results indicate that clinical use of Nutlin-3a may inhibit directional migration and have antimetastatic potential against p53 wild-type cancers, in addition to its already established antiproliferative effects.