Novel cancer chemotherapies targeting tumor-specific loss of genetic variation

The purpose of this project is to identify genetic variants that alone or in combination with hallmark chromosome level events during cancer development create drug-targetable vulnerabilities specific to tumors but not normal tissues, and designate therapies to target these as a means to treat cancer.

The specific aims of the project are to (1) identify new potential drug target genes from own multi-omics data from colorectal cancer, public data, and data from cell based screens, (2) create cell models by CRISPR-Select and overexpression to study function of the genes and potential for collateral lethality targeting, (3) use the cell models in 2D and 3D culture for drug screening to identify drugs that the cells respond differently to depending on target genotype, and (4) characterize and advance selected drug hits and targets to evaluation in human-derived organoids and animal models.

We will prioritize novel colorectal cancer driver genes, collateral lethality target genes, and genes with alternative splicing that affects extracellular epitopes. Each new target advanced to the cell model stage will be studied for several years.

We have recently provided proof-of-concept for this treatment strategy for the NAT2 and CYP2D6 genes, and have 7 new candidate targets for which we are initiating functional studies.

The project can lead to new precision treatments for cancer and improved use of existing chemotherapies through genetic biomarkers identified here.