Grant: Project Grant

Colorectal cancer is the second leading cause of cancer-related deaths in North America. Current clinical therapies used to treat colorectal cancer fail to affect a small population of malignant cells known as cancer stem cells. Such cancer stem cells drive metastasis and recurrence of the tumors. Thus, cancer stem cells are referred to as the "root of cancer" and partially depend on the patient's genetics. The degree of packaging of the DNA (known as epigenetics) also influences the maintenance of cancer stem cells in colorectal tumors. Our research aims to develop new treatments blocking epigenetic mechanisms specific to cancer stem cells without causing harm to healthy stem cells. With previous CIHR support, we discovered that a pharmacological compound initially developed to block the dopamine transporter (DAT) can suppress cancer stem cells in colorectal tumors. We found out this compound is altering epigenetic mechanisms specific and essential to cancer stem cells. Our preliminary data support the presence of DAT in colorectal cancer stem cells. Moreover, the anticancer effects of our compound of interest are mediated via DAT blockade. Thus, our proposal further investigates DAT's role in colorectal cancer stem cells. While DAT is usually found in neurons, we wish to understand why it is present in these tumors and what role it plays. So far, we have observed that partially suppressing DAT in colorectal cancer alters cancer stem cell epigenetic signature and triggers a molecular program supporting the recognition of tumor cells by the immune system. We will use cutting-edge genetic tools and patient-derived systems to strengthen our knowledge and fill the gaps in understanding DAT functions in colorectal cancer cells. Through our work, we hope to confirm DAT as a druggable target against which highly precise drugs will be developed to selectively kill colorectal cancer at its roots, which would significantly advance the efficacy of cancer cares.