University of Maryland, Johns Hopkins University, and Georgetown University researchers dig into the "BRCAness" phenotype they produced in non-small cell lung cancers treated with a low dose DNA methyltransferase inhibitor (DNMTi). The team used expression array profiling and other analyses to examine the transition from BRCA-proficient NSCLC cell lines to those resembling BRCA-mutated tumors. The results suggest that DNMTi treatment dials down the expression of genes involved in non-homologous end-joining DNA repair, which in turn makes tumors more sensitive to radiation — insights that build on past studies pointing to increased PARP inhibitor effectiveness in cancers treated with DNMTi compounds. Based on their work so far, the authors note that "significant increases in antitumor effects with DNMTi and [PARP inhibitors] in combination with [radiation therapy] suggest a potentially potent therapeutic strategy for patients with BRCA-proficient NSCLC, for whom limited therapy is available."
A University of Chicago team outlines a chemoproteomic profiling approach designed to decrease the amount of input material needed, while boosting sensitivity and speed. The method relies on a "soluble activity-dependent proximity ligation" (sADPL) strategy using chemical probes targeting multiple related proteomic players for barcoded, multiplexed analyses, the researchers explain, noting that sADPL "harnesses family-wide chemical probes to convert active enzyme levels into amplifiable barcoded oligonucleotide signals." Along with competitive sADPL profiling for quantifying drug-protein interactions in blood samples, for example, they applied the method to samples from primary tumors to assess the activity of enzymes from metabolic and proteolytic enzymes. "We expect that this modular and multiplexed chemoproteomic platform will be a general approach for drug target engagement," the authors report, "as well as comparative enzyme activity profiling for basic and clinical applications."
Researchers from the Baylor College of Medicine, Texas Children's Hospital, and the University of Texas MD Anderson Cancer Center present findings from a meningioma profiling analysis that centered on RNA sequences, exome sequences, and clinical features for 160 tumors from 140 individuals. Using these data, the team narrowed in on three meningioma molecular subtypes that appeared to line up with disease recurrence patterns, including an aggressive subgroup marked by alterations that meddle with the repressive DREAM complex to unleash cell cycle activity. The molecular groups identified "did not directly correlate with the [World Health Organization] grading system, which classifies more than half of the tumors in the most aggressive molecular subtype as benign," the investigators note.