Highlights of This Issue

Abstract

FK506-binding proteins play important roles in cancer progression. Here, Valentine and coworkers found that a secreted member of the FK506 binding protein family, FKBPL, and a potent peptide derivative, AD-01, act as highly effective inhibitors of angiogenesis in vitro and in vivo. Systemic delivery of AD-01 to tumor-bearing mice greatly reduced tumor vascularization (visualized by intravital microscopy) and effectively inhibited tumor growth. They found that AD-01 acted through a CD44-dependent mechanism to prevent migration of endothelial cells, without affecting proliferation. These findings may open a new approach to antiangiogenic therapy in cancer.CLDN4, a cell tight junction protein, is highly expressed in most ovarian cancers, but is expressed at low levels in normal tissues. Here, Gao and colleagues used the noncytotoxic small molecule C-CPE as a CLDN4- targeted delivery vehicle to selectively open cellular tight junctions and potentiate chemotherapy delivery into ovarian cancer cells. C-CPE sensitized CLDN4-expressing tumor xenografts to low-dose Taxol and suppressed tumor growth without inducing overt toxicity in animals. Further, this treatment was highly specific to CLDN4-positive ovarian cancer cells vs. CLDN4-negative cancer cells or nonneoplastic cells. This therapeutic strategy may have important implications for enhancing efficacy of conventional chemotherapy.EGFR-sensitive mutations predict improved outcome to erlotinib, but the T790M mutation can shorten the duration of response. Here, Rosell and colleagues identified a concomitant EGFR T790M mutation in a high proportion of pretreatment samples from erlotinib-treated nonsmall cell lung cancer patients. They found that, if BRCA1 mRNA expression was low, the T790M mutation did not hamper the effect of erlotinib. However, progression-free survival was significantly shorter in patients with both the T790M mutation and higher levels of BRCA1. These results suggest that initial analysis of the EGFR T790M mutation and BRCA1 mRNA expression could help predict outcome to erlotinib.Efficient predictive biomarkers are needed to enhance the responsiveness and cost-effectiveness of targeted chemotherapy. In this issue, Kim and coworkers describe a novel three-step approach of genome-wide screening, clinical association, and biological validation to identify SNP markers. Using this approach, they identified two candidate markers, LIFR rs3729740 and possibly ISX rs361863, that may help improve the prediction of metastatic colorectal cancer sensitivity to cetuximab regimens. The approach presented here could reduce the cost and time involved in conventional genome-wide association studies, and could be applied to the discovery of chemosensitive markers for new regimens.