A small molecule called TASIN-1 can selectively kill cancer cells that have a distinct mutation common in colon cancer, while still sparing related normal cells, UT Southwestern Medical Center cancer biologists have demonstrated.
The findings could eventually help with both prevention and intervention efforts for colon cancer, which according to the National Cancer Institute is the third most common type of cancer in men and women and the second leading cause of cancer-related mortality in the United States.
"Even though such mutations are common in colorectal cancer, there are currently not any therapeutics that directly target these types of mutations, so this represents fresh avenues to approach," said Dr. Jerry Shay, Professor of Cell Biology and a member of the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern. "Our latest finding confirms that targeting TASINs is a viable approach."
Using specifically engineered human colonic epithelial cells, researchers were able to screen over 200,000 small molecules using the high throughput screening core to identify TASIN-1 (truncated APC selective inhibitor). TASIN-1 is a small molecule that selectively kills cells that have a mutation in a gene called APC, or adenomatous polyposis coli. APC is a gene that suppresses the formation of tumors.
Previous research has found that the APC gene is mutated in more than 80 percent of colon tumors, and the mutations are believed to be one of the earliest events that contribute to the start of colon cancer, the researchers said.
TASIN-1 specifically kills cells with the mutated/truncated APC, but spares normal and cancer cells with the standard full length APC.
"Considering the high prevalence of APC mutations in colon cancer patients, targeting truncated APC could be an effective therapeutic strategy for prevention and intervention of colorectal cancer and could potentially be used as a marker for stratifying patients in future personalized medicine clinical trials," said Dr. Shay, The Southland Financial Corporation Distinguished Chair in Geriatrics.
After demonstrating the concept worked on cells, researchers from the Shay/Wright lab and colleagues were able to confirm the results in genetically engineered mouse models that a susceptible to colon cancer as well. The research appears in Science Translational Medicine.
Drs. Shay, Nijhawan, De Brabander are founding members of Elizabeth Therapeutics that is expanding TASIN analogues for clinical development.
This work was supported by CPRIT Grants, National Research Foundation of Korea, the Institute for Innovations in Medicine, Harold C. Simmons Cancer Center Startup Awards, a Disease Oriented Clinical Scholar (DOCS) award, a Damon Runyon Clinical Investigator award, and a grant from the Robert A. Welch Foundation, and performed in laboratories constructed with support from NIH.
Article: Selective targeting of mutant adenomatous polyposis coli (APC) in colorectal cancer, Lu Zhang, Panayotis C. Theodoropoulos, Ugur Eskiocak, Wentian Wang, Young-Ah Moon, Bruce Posner, Noelle S. Williams, Woodring E. Wright, Sang Bum Kim, Deepak Nijhawan, Jef K. De Brabander and Jerry W. Shay, Science Translational Medicine, doi: 10.1126/scitranslmed.aaf8127, published 19 October 2016.