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View the Table of Contents for the August 15 issue of Cancer Research.
Shaked et al. Page 7045
Antiangiogenic-based metronomic chemotherapy refers to prolonged administration of low doses of chemotherapy at close, regular intervals (e.g. daily or, at most, weekly) without any prolonged breaks. While very promising preclinical results have been reported, with a minimum of toxicity compared to maximum tolerated dose (MTD) regimens, relapses eventually occur. To improve outcome, Shaked et al. tested a combination of continuous, daily, low-dose oral cyclophosphamide at about 1/20 the MTD interspersed with bolus dose intraperitoneal injections of 1/3 the MTD spaced either every three or six weeks apart, in three different tumor models. Significantly improved antitumor activity, with only modest increases in toxicity, was observed in all cases.
Kobayashi et al. Page 7096
A secondary mutation of the epidermal growth factor receptor (EGFR) causes resistance to gefitinib and erlotinib and challenges the treatment of patients with non-small cell lung tumors. To characterize its mechanisms and overcome the resistance, Kobayashi et al. established cellular model systems useful for functional analyses as well as screening of alternative inhibitor drugs. Using these systems, they showed that an irreversible EGFR inhibitor, CL-387,785 can overcome drug resistance on both the biochemical as well as functional level. These data support the development of alternative EGFR inhibitor drugs for the treatment of EGFR-mutant non-small cell lung cancers.
Lusis et al. Page 7121
In a novel gene discovery approach that combines expression profiling data with known cytogenetic alterations, Lusis et al. identified NDRG2 as a candidate chromosome 14q11.2-associated tumor suppressor involved in the malignant progression of meningiomas. Additional studies validated losses of expression at both the RNA and protein levels in tumor subsets from several independent patient cohorts. The data suggest that NDRG2 is frequently inactivated in high-grade and other biologically aggressive forms of meningioma via methylation of CpG islands within the promoter region.
Ali et al. Page 7194
Glioblastoma is a devastating brain cancer for which there is no cure. It is, therefore, a good target for gene therapies. Ali et al. developed a large intracranial glioma model in which many gene therapies failed, mimicking the human scenario. The authors used a combination approach of conditional cytotoxic (HSV1-TK + ganciclovir) and immune stimulatory (Flt3L) gene therapy to induce tumor cell death and recruit antigen-presenting cells to the tumor. This method achieved long-term survival and eradication of the glioma in >70% of treated animals. Immune cells depletion experiments demonstrated that the effects of the therapy were mediated by macrophages and CD4+ T cells. The data provide the rationale for a gene therapy clinical trial for glioblastoma.
Freedman et al. Page 7516
Rare, highly penetrant germline mutations in BRCA1 strongly predispose women to familial breast and ovarian cancer. Whether common inherited variation in BRCA1 contributes to non-familial breast cancer, however, has not been thoroughly assessed. To explore whether common variation at this locus contributes to sporadic breast cancer, Freedman et al. performed a comprehensive analysis of the BRCA1 gene in a large case-control study in the Multiethnic Cohort. In this study, linkage disequilibrium and haplotype patterns across five ethnic groups were empirically determined across the BRCA1 locus and were tested for association to breast cancer risk. No significant associations were observed between common genetic variation at this locus and breast cancer risk in this multiethnic population. These results indicate that common BRCA1 alleles do not substantially influence the development of breast cancer in the general population.