Identification of APC Synthetic Lethal Targets for FAP Treatment
Andres Blanco, PhD
Assistant Professor of Biomedical Sciences
Identification of APC Synthetic Lethal Targets for FAP Treatment
Familial adenomatous polyposis (FAP) is an inherited condition in which tens to thousands of small growths – or, polyps – form in the rectum and colon in early adulthood. If FAP is left untreated, colorectal cancer (CRC) will develop in almost 100% patients by age 40. Due to this concern, FAP patients are subjected to annual colonoscopies and potentially to prophylactic surgery to prevent CRC. A potential alternative to surgical intervention is chemopreventative treatment – treatment with agents that prevent progression to CRC. While attractive in principle, successful chemopreventative approaches have not yet been developed. Here, we propose an approach to lay the groundwork for a novel type of chemoprentative FAP treatment. Our method is focused on a gene called APC – which is the gene that is universally mutated in FAP. We suspect that the APC mutation creates novel cellular vulnerabilities – or, cellular Achilles’ heels that are unique to the FAP cells – that can be targeted with drugs. Here, we will use the Nobel prize-winning CRISPR-Cas9 methodology to identify these genes that, upon inhibition of the proteins they encode, will prevent FAP progression to CRC. We will test the drugs we find using cellular models of FAP – colon cells with the APC mutation that can be grown on Petri dishes. If we are successful, colon cells treated with the drug(s) will retain normal growth properties, rather than growing dangerously fast and progressing toward CRC. In this case, such a drug could potentially be used for chemoprevention of CRC in FAP patients.
