Highlights of This Issue

Abstract

The clinical suppression of the EWS-FLI1 transcription factor has not been achieved despite a known dependence of Ewing sarcoma on this target. Osgood and colleagues previously demonstrated that the DNA-binding compound mithramycin blocks the activity of the EWS-FLI1 transcription factor to suppress tumor growth in preclinical models. Unfortunately, the clinical translation of this compound as an EWS-FLI1–directed therapy was limited by toxicity. In this study, the authors optimized the structure of mithramycin and identified two second-generation analogues that maintain suppression of EWS-FLI1 but have improved toxicity profiles.Clinical testing of FLT3 inhibitors in children with relapsed leukemia has been limited by off-target toxicity and an inability to achieve sustained inhibition. Cooper and colleagues report the results of a phase I clinical trial using the second-generation FLT3 inhibitor, quizartinib, combined with chemotherapy for relapsed pediatric leukemia. The authors demonstrate that quizartinib is well tolerated, provides sustained inhibition of FLT3 phosphorylation, and shows promising therapeutic activity in children with FLT3 mutations.Modification of tumor hypoxia may improve radiotherapy for cervical cancer; however, methods for classifying patients according to hypoxia are required for evaluation of adjuvant hypoxia-modifying drugs. Fjeldbo and colleagues combined DCE-MRI and gene-expression profiles of cervical cancer patients to construct an image-associated, hypoxia gene classifier for stratifying hypoxic tumors. The robustness of the classifier was demonstrated by successful validation of its hypoxia association and prognostic value across cohorts and assay platforms. The classifier shows promise as a genomic tool to aid treatment decision making both alone and for future integration with DCE-MRI.Zheng and colleagues report that histone deacetylase (HDAC) inhibitors increase the expression of multiple T-cell chemokines in cancer cells, macrophages, and T cells. In vivo, the HDAC inhibitor romidepsin increased chemokine expression and enhanced T-cell infiltration and T-cell–dependent tumor regression. Furthermore, romidepsin enhanced responses to PD-1 blockade immunotherapy in lung cancer. These results suggest that HDAC inhibitors can be used to increase T-cell infiltration into tumors and, in combination with PD-1 blockade, can enhance immunotherapy.