ColoType: a forty gene signature for consensus molecular subtyping of colorectal cancer tumors using whole-genome assay or targeted RNA-sequencing.

Colorectal cancer (CRC) tumors can be partitioned into four biologically distinct consensus molecular subtypes (CMS1-4) using gene expression. Evidence is accumulating that tumors in different subtypes are likely to respond differently to treatments. However, to date, there is no clinical diagnostic test for CMS subtyping. In this study, we used novel methodology in a multi-cohort training domain (n = 1,214) to develop the ColoType scores and classifier to predict CMS1-4 based on expression of 40 genes. In three validation cohorts (n = 1,744, in total) representing three distinct gene-expression measurement technologies, ColoType predicted gold-standard CMS subtypes with accuracies 0.90, 0.91, 0.88, respectively. To accommodate for potential intratumoral heterogeneity and tumors of mixed subtypes, ColoType was designed to report continuous scores measuring the prevalence of each of CMS1-4 in a tumor, in addition to specifying the most prevalent subtype. For analysis of clinical specimens, ColoType was also implemented with targeted RNA-sequencing (Illumina AmpliSeq). In a series of formalin-fixed, paraffin-embedded CRC samples (n = 49), ColoType by targeted RNA-sequencing agreed with subtypes predicted by two independent methods with accuracies 0.92, 0.82, respectively. With further validation, ColoType by targeted RNA-sequencing, may enable clinical application of CMS subtyping with widely-available and cost-effective technology.

Discovery and Structural Optimization of Acridones as Broad-Spectrum Antimalarials.

Malaria remains one of the deadliest diseases in the world today. Novel chemoprophylactic and chemotherapeutic antimalarials are needed to support the renewed eradication agenda. We have discovered a novel antimalarial acridone chemotype with dual-stage activity against both liver-stage and blood-stage malaria. Several lead compounds generated from structural optimization of a large library of novel acridones exhibit efficacy in the following systems: (1) picomolar inhibition of in vitro Plasmodium falciparum blood-stage growth against multidrug-resistant parasites; (2) curative efficacy after oral administration in an erythrocytic Plasmodium yoelii murine malaria model; (3) prevention of in vitro Plasmodium berghei sporozoite-induced development in human hepatocytes; and (4) protection of in vivo P. berghei sporozoite-induced infection in mice. This study offers the first account of liver-stage antimalarial activity in an acridone chemotype. Details of the design, chemistry, structure-activity relationships, safety, metabolic/pharmacokinetic studies, and mechanistic investigation are presented herein.