TP53 Synthetic Lethal Screen in Organoid Avatars to Discover Novel Therapeutic Targets for Colon Cancer
Abstract
TP53 mutations are common in colon cancers (50%), and most often lead to resistance to chemotherapy such as Cisplatin. TP53 mutations almost always inactivate the gene. This often results in a cell that has some type of selective advantage over its wild-type ancestors by escaping cell death. It is theoretically possible that having no functional p53 may create a cell that is dependent on the function of another gene for survival in the presence of chemotherapy. An Achilles Heel, to be exploited if only we can find Paris Arrow. We will use CRISPR/CAS9 gene editing technology to create a population of colon cancer cells that have p53 mutations, and then find new ways to kill or inhibit the growth of the cells with p53 mutations in the presence of chemotherapy, while simultaneously making sure these methods do no harm to the cells with functional p53. This project is to figure out how to make cancer cells sensitive to chemotherapy drugs to which they have become resistant through p53 mutation. We will use our TP53 gene knockout colon cancer organoids to test 129 cancer drugs and find out which drugs do not work and why. Notably, Cisplatin, Oxaliplatin, Irinotecan, and Olaparib all fail to work at inhibiting cell growth when p53 is mutated. We will perform a genome-wide knockout screen IN THE PRESENCE OF CHEMOTHERAPY DRUGS to identify those other genes that, when knocked out, re-sensitize TP53 mutant cells to the chemotherapy. The results of these studies will produce novel targets for the treatment of TP53 mutant colon cancer and will identify novel combination therapies that rescue the use of one or more first line cancer drugs that are rendered ineffective by mutant TP53. This research will lead to novel treatments for over half of colon cancers by targeting genes required for survival in the absence of functional TP53. In the future, this pipeline will be extended to test each patients own tumor versus normal in the presence of chemotherapy, and discover personalized ways to repurpose ineffective drugs.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910847
Entities
People
- Phillip Buckhaults
Organizations
- United States Army
- University of South Carolina