Targeting regenerative reprogramming in colorectal cancer

The project aims to characterize the preexisting (pre-resistant) state using barcode lineage tracing and single-cell technologies. It will study the contribution of preexisting versus actively gained fitness features through whole-exome (WES) and RNA sequencing (RNA-seq) using patient-derived organoids (PDOs). The research will define the role of genetic and non-genetic drivers of tumor escape using pre-clinical models of resistance to KRAS-inhibition (KRASi). A focused shRNA screen targeting 50 chromatin regulators will be performed to develop approaches that abrogate regenerative reprogramming. Readily available compounds targeting the top hits of the screen will be tested in combination with standard therapies to expedite clinical translation. The candidate will conduct this research at Weill Cornell Medicine (WCM) and Memorial Sloan Kettering (MSK) under mentorship, committing at least 9 person-months of professional effort to a 5-year plan.