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Targeting colorectal cancer-initiating cells and anti-EGFR therapeutic resistance by manipulating levels of the reactive aldehyde, 4-hydroxynonenal.

Catherine O'Brien

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Canadian Institutes of Health Research (CIHR)
Colorectal cancer (CRC) is the 2nd leading cause of cancer mortality in Canada, with 9,200 deaths annually. We have previously shown that CRCs are initiated and maintained by a subset of colorectal cancer-initiating cells (CC-ICs). There is also increasing evidence in a number of solid tumors that cancer-initiating cells are preferentially chemoresistant. Therefore it is important to understand the biology of these cells in order to develop methods to specifically target the CC-IC subset. In preliminary work we have shown that CC-ICs are very sensitive to the level of the reactive aldehyde, 4-hydroxynonenal (4-HNE). Increased levels of 4-HNE results in increased CC-IC death and potentiates the response to cetuximab, an EGFR-targeted therapy commonly used in the treatment of colorectal cancer. There are existing drugs, already approved for other purposes, that increase 4-HNE levels and it is our plan to use these drugs in combination with cetuximab to develop new therapeutic strategies directed at improving patient outcome for CRC patients.

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