Highlights of This Issue

Abstract

Aberrant expression of inducible nitric oxide synthase (iNOS) in the tumor microenvironment has been linked to progression, metastasis, and poor prognosis of human cancers, including cutaneous melanoma. Here, Sikora and colleagues tested the efficacy of iNOS-directed targeted therapy for the treatment of established human melanoma xenografts in SCID/NOD mice. Oral treatment with the iNOS-selective small molecule antagonist N6-(1-Iminoethyl)-L-lysinedihydrochloride (L-nil) inhibited melanoma growth, decreased formation of intratumoral microvessels, and enhanced the efficacy of cisplatin chemotherapy. These data support the hypothesis that iNOS expression supports tumor growth in vivo and suggest targeted iNOS inhibition is a promising therapeutic approach.Although there are hundreds of drugs currently in development for cancer, a number of constraints limit the ability of researchers to effectively evaluate all of these agents in Phase I trials. In this issue of CCR Focus, guest editors Patricia LoRusso and Lesley Seymour explore some of the barriers related to Phase I clinical trials, and discuss strategies for managing and overcoming these barriers. Some of the topics addressed include different approaches to Phase I trial design, the incorporation of biomarkers into early trials, good practices for data collection and reporting, and requirements for preclinical testing prior to conducting a first-in-human trial.The CpG island methylator phenotype (CIMP) represents a subgroup of colorectal cancers characterized by frequent promoter hypermethylation. Here, Dahlin and colleagues investigated the impact of this phenotype on patient prognosis in two large patient groups. Compared to patients with CIMP-negative tumors, CIMP-low tumor patients had poorer survival, regardless of the status of microsatellite instability screening. CIMP-high tumor patients, on the other hand, had poorer survival only in the context of microsatellite stable colorectal cancer. These findings contribute to an increased understanding of molecular subtypes and prognostic factors in colorectal cancer.A large proportion of BRCA gene variants have unknown clinical significance. To investigate the effect of BRCA DNA variants on splicing efficiency, Sanz and colleagues developed a strategy combining electronic prediction and RT-PCR–based functional splicing assays of lymphocyte mRNA or hybrid minigenes in HeLa and MCF10A cells. Anomalous RNA processing was observed in 28 out of the 57 assayed variants, and variants affected splice sites and splicing enhancers and silencers. Aberrant splicing may therefore represent a relevant pathogenic mechanism in hereditary breast/ovarian cancer, and further study of these splicing defects may increase the proportion of families that benefit from genetic counselling.