Highlights of This Issue

Abstract

Retinoid resistance is common in most solid tumors, including pancreatic adenocarcinoma. Gupta and colleagues show that the majority (∼80%) of pancreatic cancers are likely to be resistant to retinoic acid due to the tumorspecific overexpression of fatty acid–binding protein-5 (FABP5), which channels all-trans retinoic acid (ATRA) into survival and proliferation pathways. On the contrary, approximately 20% of cases that lack FABP5 expression but are characterized by high levels of cellular retinoic acid–binding protein-2 (CRABP2), retain retinoid sensitivity. A simple immunohistochemical assay can identify the subset of FABP5-negative tumors most likely to benefit from ATRA therapy in settings such as gemcitabine resistance.Immunosuppressive phenotype and infiltrative growth into the surrounding brain tissue are characteristic features of malignant gliomas. Such factors as TGF-β are relevant in both processes. Here, Lemke and colleagues show that 4IgB7H3, a member of the B7-family of costimulatory proteins, has similar properties that function in a TGF-β–independent manner. Clinically, expression of B7H3 in human glioma correlates with the grade of malignancy and is associated with worse clinical outcome. Mechanistically, the active immunosuppressive and proinvasive form of 4IgB7H3 is released into the supernatant in glioma, whereas in other tumors and dendritic cells the membrane-bound form has been found to be active. Thus, 4IgB7H3 has potential as a diagnostic and therapeutic target in malignant glioma.Follicular cystic lesions, keratoacanthomas, and squamous cell carcinomas, all seemingly originating from hair follicles, frequently occur in patients treated with sorafenib. More than 30% of these lesions harbor oncogenic, potentially UV-induced HRAS, TGFBR1, or TP53 mutations. Sorafenib, like other BRAF inhibitors, induces a paradoxical increase in keratinocyte proliferation and MAP kinase pathway activation due to BRAF/CRAF dimerization and CRAF activation. The findings reported by Arnault and colleagues have major implications because they suggest that other cells with wild-type BRAF carrying a somatic event like a RAS mutation could be transformed by sorafenib or other BRAF inhibitors in vivo.TP53 is the most commonly mutated gene in head and neck squamous cell carcinoma (HNSCC); however, its use as a prognostic marker is controversial. Skinner and colleagues found that a class of TP53 mutations (“disruptive”) was predictive for higher locoregional failure in patients treated with radiation, who showed increased in vitro radioresistance and decreased rates of senescence. They observed that HNSCC cells harboring disruptive TP53 could be selectively radiosensitized with metformin both in vitro and in vivo. Also, metformin use was associated with decreased locoregional failure in patients following radiation. These data suggest that TP53 is a promising biomarker to predict local failure and that metformin is a potential agent to target these tumors.