Highlights of This Issue

Abstract

In contrast with exon 19 deletions in the epidermal growth factor receptor (EGFR) gene, insertions in exon 19 are uncommon, and their association with EGFR tyrosine kinase inhibitor (TKI) sensitivity in lung adenocarcinoma is uncertain. He and colleagues report on a multifaceted analysis of this mutation, including clinical characteristics in the largest set of patients assembled to date, modeling of mutant protein structure, assessment of in vitro sensitivity, and review of EGFR TKI clinical response data. They show that exon 19 insertions lend TKI sensitivity, a finding that supports the clinical importance of identifying these insertions in exon 19 in addition to the more common deletions.To explore aberrations related to progression in myxofibrosarcoma, Li and colleagues identified an amplified SKP2 gene on 5p by array comparative genomic hybridization. In myxofibrosarcoma tissues, SKP2 mRNA was upregulated, and gene amplification was detected in 38% of independent cases, which was associated with SKP2 expression and worse patient survival. Besides promoting cell proliferation, SKP2 was confirmed to confer prometastatic propensity, probably via upregulated expression of motility-promoting genes, including ITGB2, ACTN1, IGF1, and ENAH. Bortezomib treatment showed an SKP2-suppressing effect and induced apoptosis at a low dose in myxofibrosarcoma cell lines and xenografts, highlighting the clinical and therapeutic relevance of SKP2 in myxofibrosarcoma.Interleukin (IL)-2 is a proinflammatory cytokine with potent antitumor activity. However, systemic delivery of IL-12 is associated with severe toxicities that preclude its clinical use. Chinnasamy and colleagues explored a novel way of delivering IL-12 into solid tumors by adoptive transfer of T cells modified to coexpress an inducible Il12 gene and a chimeric antigen receptor targeting the VEGF receptor (VEGFR)-2 protein on the vasculature of solid tumors. The anti-VEGFR2 chimeric antigen receptor (CAR) and inducible IL-12–engineered T cells induced regression of a variety of established tumor types in mice without causing toxicity. This study provides a rationale for using engineered T cells to target tumor vasculature and to enhance the therapeutic index of IL-12 for the treatment of cancer.CEN-209 is a bioreductive prodrug designed to target tumor hypoxia. Metabolic activation of CEN-209 depends on unidentified reductases in hypoxic cells. Wang and colleagues investigated whether the 2-nitroimidazole, EF5, a hypoxia probe in clinical development, might act as a dual reporter for hypoxia and CEN-209 reductases. CEN-209 metabolism and covalent binding of EF5 were shown to be highly correlated in human tumor cell lines, and EF5 binding was predictive for CEN-209 sensitivity in individual human tumor xenografts. The results of this study support the use of positron emission tomographic imaging with [18F]-EF5 as a companion diagnostic (stratification biomarker) for clinical development of CEN-209.