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Apr 15, 2014

Targeting MicroRNA for Colorectal Cancer Therapy

  • An international team of researchers reports that microRNA-135b plays a critical role driving the growth of bowel cancers. Drugs targeted at the microRNA could knock out the effects of multiple cancer-causing mutations at once, while tests for it could identify patients with the most aggressive disease, according to the scientists.

    The study (“MicroRNA-135b Promotes Cancer Progression by Acting as a Downstream Effector of Oncogenic Pathways in Colon Cancer”), which was carried out by scientists based at the Institute of Cancer Research, London, the University of Glasgow, and Ohio State University, among others, appears in Cancer Cell.

    The teams tested for microRNA-135b in 485 patients with bowel cancer and found that levels were at least four times as high in tumors as in healthy tissue, and that patients with the highest levels survived the least long. They showed that blocking the microRNA stopped tumor growth in bowel cancer mouse models, and in half of them tumors regressed so dramatically they could no longer be seen by imaging. Mice didn't show any side effects as a result of treatment.

    The study demonstrated that a number of known cancer gene mutations, such as APC, PI3KCA, SRC, and p53, exercise their effects through microRNA-135b.

    “We show that miR-135b overexpression is triggered in mice and humans by APC loss, PTEN/PI3K pathway deregulation, and SRC overexpression and promotes tumor transformation and progression,” wrote the investigators. “We show that miR-135b upregulation is common in sporadic and inflammatory bowel disease-associated human CRCs [colorectal cancers] and correlates with tumor stage and poor clinical outcome. Inhibition of miR-135b in CRC mouse models reduces tumor growth by controlling genes involved in proliferation, invasion, and apoptosis. We identify miR-135b as a key downstream effector of oncogenic pathways and a potential target for CRC treatment.”

    Although treatments targeting bowel cancer mutations have been developed, patients often develop resistance. Inhibiting microRNA-135b could be an exciting way to attack cancers without resistance occurring by blocking the effects of multiple cancer-causing mutations simultaneously, explained Nicola Valeri, leader of the Gastrointestinal Cancer Biology and Genomics Team at the Institute of Cancer Research, London.

    “The findings also suggest that testing levels of microRNA-135b could help identify patients likely to develop aggressive bowel cancer, and who might need the most intensive treatment,” he added.



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