Highlights of This Issue

Abstract

Foretinib is a multikinase inhibitor that targets tumor proliferation through inhibition of Met, and angiogenesis through inhibition of VEGFR2, Tie-2, and PDGF. Eder and colleagues performed a first-inhuman, phase I, dose-escalation trial of oral foretinib. They established that a dose up to 3.6 mg/kg for 5 consecutive days of a 14-day cycle was acceptable for phase II trials. Furthermore, this dose and schedule demonstrated significant evidence of biologic activity and clinical efficacy. Reversible elevations in serum AST and lipase were the dose-limiting toxicities. These findings support plans to investigate alternative schedules, and to explore activity where Met or angiogenesis drive tumors.Stratification of melanoma patients into subclasses based on molecular patterns could lead to more accurate prognosis and prediction of treatment response. Jönsson and colleagues used global expression profiling to classify stage IV melanomas into four subtypes. Different subtypes were associated with distinct biological parameters such as pigmentation and immune response. Importantly, the classification displayed significant correlation to clinical outcome, with the proliferative subtype predicting a poor prognosis. This molecular classification scheme should be explored further for application to the prognosis and treatment of metastatic melanoma patients.VEGF signaling is active in chronic lymphocytic leukemia (CLL) and is likely to play a critical role in cell-microevironment interactions. In this issue, Paesler and colleagues demonstrate that two VEGF receptor tyrosine kinase inhibitors, vatalanib and pazopanib, possess a direct cytotoxic effect on CLL cells, which is mediated via regular apoptotic signaling. Low concentrations of each drug combined with conventional cytostatics like fludarabine resulted in an additive effect. Further, both compounds led to a substantial tumor reduction in a CLL-like xenograft nude mouse model. These findings serve as a rationale to test vatalanib and pazopanib, either alone or combined with conventional cytostatics, in human CLL.Limited information is available regarding glioma etiology and prognostic factors that influence patient survival. Using a novel murine glioma model, Fujita and colleagues show here that the absence of type-1 interferon (IFN) signaling caused dynamic changes in the immunological microenvironment of murine gliomas, thereby accelerating tumor growth. These data led to the identification of SNPs in IFNAR1 and IFNA8 that were associated with altered survival of glioma patients. This study demonstrates how a multipronged approach using both a murine model and human genetics may foster the identification of novel risk and/or prognostic factors for gliomas.