HOUSTON — (March 26, 2018) — A study conducted at the Departments of Biochemistry (Jef De Brabander) and Cell Biology (Jerry Shay), University of Texas Southwestern Medical Center, Dallas, TX has demonstrated that TASIN (Truncated APC Selective INhibitor), a recently identified small molecule, selectively kills colorectal cancer cells (CRC) by inducing endoplasmic reticulum (ER) stress which leads to activation of the pro-apoptotic JNK pathway and PARP cleavage. The ER is a central organelle involved in protein folding, protein maturation and lipid synthesis. Interference in ER homeostasis, results in an accumulation of misfolded or unfolded proteins in the ER lumen. In addition, TASIN inhibits pro-survival, AKT activity through a cholesterol-dependent manner in CRC cells. The research was published in the journal Molecular Cancer Therapeutics (Mol Cancer Ther. 2018 Feb 21. pii: molcanther.0887.2017. doi: 10.1158/1535- 7163.MCT-17-0887. [Epub ahead of print]).
Mutation of the APC tumor suppressor gene is a frequent and early, if not initiating, event in CRC tumorigenesis, and present in about 80% of all CRC tumors. TASIN induces ER stress and oxidative stress due to intracellular cholesterol depletion, specific to truncated APC-expressing cells.
“Our results reveal the downstream mechanism which drives TASIN induced apoptotic cell death in truncated APC cells. This knowledge could aid in the future clinical development of TASIN as a novel targeted therapeutic strategy for colorectal cancer patients.” said Jerry W. Shay, senior author of the study, and professor of Cell Biology at UT Southwestern Medical Center.
TASIN had previously been shown to have synthetic lethality in CRC cells expressing truncated APC, while sparing normal cells expressing wild-type APC. The compound induces cell death through depletion of cholesterol in truncated APC cells. However, the downstream mechanism in response to TASIN induced cholesterol depletion were unknown prior to these studies.
“TASIN is a fascinating innovative drug candidate that selectively kills colon cancer cells without harming healthy cells, and it may be the first truly targeted compound for CRC,” said Frank Perabo, CEO of Barricade. “These data expand our understanding and knowledge around the mode of action of TASIN and support our efforts to advance this compound to clinical trials.”
This work was supported by CPRIT (Cancer Prevention Research Institute of Texas) grants.
TASIN (Truncated APC Selective INhibitor), is a small molecule drug that specifically targets the truncated APC gene mutation in colorectal cancer. TASIN is a genotype-selective compound that has synthetic lethality within the cholesterol biosynthesis pathway specifically in truncated APC cells in vitro and in vivo, with no apparent toxicity to normal cells. Barricade Therapeutics is developing TASIN for colorectal cancer and holds the worldwide exclusive license.
About Barricade Therapeutics:
Barricade Therapeutics, Corp. is a privately-held Biotech company based in Houston, TX. Barricade was founded based on discovery and advancement of novel first-in-class anti-cancer small molecules. The current status of the development programs is nonclinical.