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.