Colorectal cancers (CRC) that develop from polyps on the inner lining of the colon or rectum are remain the second leading cause of cancer-related mortality in the US, with 53,200 deaths expected in 2020. The lifetime risk of colorectal cancer is about 1 in 23 (4.4%) for men and 1 in 25 (4.1%) for women. The current standard of care for CRC is surgical resection to whatever extent is possible, followed by radiation, chemotherapy and/or immunotherapy. The predominant chemotherapy used in standard clinical care is 5-fluorouracil. Unfortunately, numerous patients, especially those with metastatic disease, will develop chemoresistance to 5-fluorouracil eventually leading to treatment failure.
Previous research indicates that 5-fluorouracil resistance is linked to an increase in the cytoplasmic abundance of a gene regulatory protein called Nuclear factor erythroid 2-related factor 2 (Nrf2). Nrf2 regulates several antioxidant genes when within the nucleus, however this protein also contributes to CRC tumor invasion and the development of 5-fluorouracil resistance when abundant in cytoplasm mainly due to the activation of NF-kB/AKT/b-catenin/ZEB1 signaling from Nrf2-induced proteasome 26A subunit, non-ATPase 4 (PSMD4) expression. And, this signaling cascade is involved in epithethelial-to-mesenchymal transition-mediated cellular chemoresistance.
NDT is developing NDT-59, a first-in-class, small molecule compound that suppresses cellular growth in Nrf2 expressing CRC cancerous cells, including those that are 5-fluorouracil resistant. 75% of CRC patients have cytoplasmic Nrf2 expressing tumors with unfavorable response to 5-fluorouracil. Thus far, NDT-59 has proven effective when used against two colon cancer cell lines, HCT-15 & HT-29. Importantly, the growth of Nrf2-induced xenograft tumors in mice were completely suppressed when using NDT-59. Excitingly, the degree of this growth suppression by NDT-59 was similar to the activity of a combination treatment using both 5-fluorouracil and carfilzomib together.