A target for the treatment of all types of cancer
The results of the study by a team from the University of British Columbia and the Cancer Research Institute of British Columbia, Canada, led by Professor Shoukat Dedhar, are likely to help create new strategies for the treatment of solid tumors, which include most tumors that occur in the body.
Solid tumors need an active blood supply to obtain oxygen and nutrients that help them grow and metastasize quickly. As it progresses, the blood vessels are unable to provide oxygen and nutrients to the entire tumor, which leads to the formation of areas with low oxygen content. Over time, inside the tumor cells in this hypoxic niche, the pH shifts to the acidic side. To overcome this stress, cells adapt by releasing enzymes that neutralize the acidic environment. This allows them to survive and even become more aggressive towards the body. One of these enzymes is carbonic anhydrase IX (CAIX).
The CAIX enzyme is vital for cancer cells, but this dependence makes it an ideal target for therapy. If you suppress its activity, you can effectively stop the growth of cells.
Professor Shoukat Dedhar and his colleagues have previously identified a unique compound SLC-0111, which is currently being evaluated in Phase 1 clinical trials as a potent CAIX inhibitor. In preclinical studies on animal models of breast cancer, pancreas and brain tumors, SLC-0111 demonstrated efficacy in suppressing tumor growth and spread, but unknown cellular properties reduced its effectiveness.
In this study, the team studied these cellular properties and identified other weaknesses of the CAIX enzyme using a powerful method – genome-wide synthetic lethal screening. This tool studies the DNA of a cancer cell and systematically removes one gene at a time to determine if it is possible to kill a cancer cell by removing the CAIX enzyme along with another specific gene.
The results pointed to the unexpected role of proteins and processes that control ferroptosis – cell death due to iron accumulation, leading to inhibition of cancer cell metabolism and damage to cell membranes.
Thus, the CAIX enzyme blocks the death of cancer cells as a result of ferroptosis. The combination of CAIX inhibitors, including SLC-0111, with compounds that cause ferroptosis will lead to rapid cell death and stop tumor growth.
Currently, laboratories in different countries are making efforts to detect drugs that can cause ferroptosis.
Article by S.C.Chafe et al. Genome-wide synthetic lethal screen unveils novel CAIX-NFS1/xCT axis as a targetable vulnerability in hypoxic solid tumors published in the journal Science Advances.
Amina Ibragimova, portal "Eternal Youth" http://vechnayamolodost.ru based on the materials of the University of British Columbia: New study examines 'Achilles' heel' of cancer tumours, paving the way for new treatment strategies.