WR 238605, chloroquine, and their combinations as blood schizonticides against a chloroquine-resistant strain of Plasmodium vivax in Aotus monkeys

The compound WR 238605 is a primaquine analog being developed by the U.S. Army as an antimalarial drug. Currently, there is no established treatment for Plasmodium vivax parasitemias that are not cured by chloroquine. This study tested WR 238605, chloroquine, and their combinations against a chloroquine-resistant strain of P. vivax (AMRU 1) in Aotus monkeys. A total dose of 3 mg/kg of WR 238605 given at a dosage of 1 mg/kg/day for three days cleared patent parasites in all eight monkeys but recrudescence of parasitemia occurred 15-25 days after initiation of treatment. A total dose of 9 mg/kg of WR 238605 over a three-day period cured all three monkeys of their infections. A total dose of 30 mg/kg of chloroquine did not clear patent infections in three monkeys, whereas a total dose of 60 mg/kg generally (two of three) cleared patent parasitemia but did not cure. Whereas total doses of 30 mg/kg of chloroquine or 3 mg/kg of WR 238605 given alone failed to cure, both drugs given in combination at these dosages cured two of three infections. These results indicate that WR 238605 may be an alternative treatment for chloroquine-resistant vivax malaria

The mutational landscapes of genetic and chemical models of Kras-driven lung cancer

Next-generation sequencing of human tumours has refined our understanding of the mutational processes operative in cancer initiation and progression, yet major questions remain regarding factors that induce driver mutations, and the processes that shape their selection during tumourigenesis. We performed whole-exome sequencing (WES) on adenomas from three mouse models of non-small cell lung cancer (NSCLC), induced by exposure to carcinogens (Methyl-nitrosourea (MNU) and Urethane), or by genetic activation of Kras (Kras(LA2)). Although the MNU-induced tumours carried exactly the same initiating mutation in Kras as seen in the Kras(LA2) model (G12D), MNU tumours had an average of 192 non-synonymous, somatic single nucleotide variants (SNVs), compared to only 6 in tumours from the Kras(LA2) model. In contrast, the Kras(LA2) tumours exhibited a significantly higher level of aneuploidy and copy number alterations (CNAs) compared to the carcinogen-induced tumours, suggesting that carcinogen and genetically-engineered models adopt different routes to tumour development. The wild type (WT) allele of Kras has been shown to act as a tumour suppressor in mouse models of NSCLC. We demonstrate that urethane-induced tumours from WT mice carry mostly (94%) Q61R Kras mutations, while those from Kras heterozygous animals carry mostly (92%) Q61L mutations, indicating a major role of germline Kras status in mutation selection during initiation. The exome-wide mutation spectra in carcinogen-induced tumours overwhelmingly display signatures of the initiating carcinogen, while adenocarcinomas acquire additional C>T mutations at CpG sites. These data provide a basis for understanding the conclusions from human tumour genome sequencing that identified two broad categories based on relative frequency of SNVs and CNAs(1), and underline the importance of carcinogen models for understanding the complex mutation spectra seen in human cancers