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This Week in the British Journal of Cancer: Jul 17, 2012

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In the British Journal of Cancer this week, researchers in Japan present their investigation of KRAS mutations in both primary tumors and post-treatment metastatic lesions in cases of colorectal cancer. The researchers analyzed a total of 63 lesions — 23 baseline primary, 18 metastatic, and 24 post-treatment metastatic — from 21 patients who underwent FOLFOX adjuvant therapy. From that, they found that the mutational status of KRAS remained concordant between primary tumors and post-treatment metastatic lesions. Further, the mutations status of NRAS, BRAF, and PIK3CA were also concordant between primary and metastatic lesions. "Because the mutational statuses of predictive biomarker genes were not altered by FOLFOX therapy, specimens from both primary tumors and post-FOLFOX tumor metastases might serve as valid sources of DNA for known genomic biomarker testing," the researchers writes.

Also in the British Journal of Cancer this week, researchers at the University of Oxford and Vertex Pharmaceuticals describe their efforts to target radiation-resistant hypoxic tumor cells with ATR inhibition. The researchers used a highly selective ATR inhibitor developed by Vertex called VE-821 to stop ATR-mediated signaling in response to replication arrest induced by severe hypoxia in cancer cells. "Consistently, ATR inhibition sensitized tumor cell lines to a range of oxygen tensions," the authors write. "Most importantly, VE-821 increased radiation-induced loss of viability in hypoxic conditions. Using this inhibitor we have also demonstrated for the first time a link between ATR and the key regulator of the hypoxic response, HIF-1."

Finally in the British Journal of Cancer this week, a team at the University of Texas at Arlington reports that mixed lineage leukemia-4 regulates cell-cycle progression and cell viability, while its depletion suppresses the growth of xenografted tumors in vivo. The team's study shows that knocking down MLL4, an H3K4-specific methyl transferase, affects cell-cycle progression and induces apoptotic cell death in cultured tumor cells. It also "induced nuclear condensation, fragmentation, cytochrome-c release from mitochondria to cytosol and activated caspase-3/7 indicating apoptotic cell death," the team writes. "MLL4 regulates expression of various critical cell-cycle regulatory genes such as cyclin D, cyclin E, p27, HOXA5 and HOXB7 via histone H3K4 trimethylation and recruitment of RNA polymerase II." Further, in a mouse model of colon cancer, application of MLL4 antisense suppressed tumor growth.

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