Highlights of This Issue

Abstract

HDAC inhibitors have been shown to modulate immune response in preclinical models. To explore the immunomodulatory activity of HDAC in the clinical setting, Pili and colleagues designed a phase I/II clinical study with the selective class I inhibitor entinostat and high-dose IL2 in patients with metastatic clear cell renal cell carcinoma. The combination resulted in greater objective response rate and increased median progression-free survival compared to historical data. This proof of principle provides the rationale for further clinical testing of this epigenetic modulator and immunotherapies as rational combination strategies.PARP inhibitors (PARPi) have emerged as an intriguing treatment strategy for patients with Ewing sarcoma (ES), but have yet to demonstrate responses in clinical trials. Heske and colleagues performed a high-throughput matrix drug screen to identify novel, synergistic drug combinations in ES and found that combining PARPi with NAMPT inhibitors, which block the rate-limiting step in NAD+ production, was a rational approach to enhancing PARP inhibition. This combination resulted in robust synergy in vitro through decreased PAR activity and increased DNA damage, and retained efficacy in vivo, suggesting that this combination may be a promising strategy for ES.Hu and colleagues identify a novel application of plasma cell-free DNA (cfDNA) genotyping, widely used as a cancer diagnostic, to study the germline genetics of cancer patients. Germline and somatic EGFR T790M mutations are used as a clinical model to develop methods for differentiating germline and somatic variants within plasma cfDNA. Using a database of 31,414 subjects undergoing plasma next-generation sequencing (NGS), they demonstrate that germline EGFR T790M mutations are enriched in lung cancer, but not other cancer types. Awareness is needed of the potential for clinically important incidental germline findings from plasma NGS.Hyperactivation of the Wnt/β-catenin and PI3K/Akt signaling pathways has limited clinical benefit mostly due to unknown resistance mechanisms and the lack of predictive biomarkers of the drug response. Kang and colleagues investigated molecular crosstalk between the Wnt/β-catenin and PI3K/Akt pathways via ICAT, a negative regulator of Wnt/β-catenin signaling. The authors provide evidence for a rational stratification of patients hyperactivated by the Wnt/β-catenin and PI3K/Akt signaling pathways using PLD1 and ICAT as predictive targets of the drug response. These results may assist in the clinical development of a PLD1 inhibitor for treatment of CRC patients carrying APC and PI3KCA mutations.