A new study opens up prospects for treating one of the deadliest forms of pancreatic cancer, after researchers successfully disrupted the growth and spread of cancer cells using experimental compounds that target a gene linked to disease development.
Pancreatic ductal adenocarcinoma is the most common type of pancreatic cancer, and it is also among the most difficult cancers to treat due to its rapid spread and resistance to available treatments.
The majority of this cancer cases are linked to mutations in the KRAS gene, which plays a key role in regulating cell growth. When this gene mutates, cells begin to divide uncontrollably, leading to tumor formation. For decades, researchers considered targeting this gene with drugs to be extremely challenging, even describing it as "pharmacologically untargetable."
In an attempt to overcome this obstacle, a team from the College of Pharmacy and Pharmaceutical Sciences at Florida A&M University tested experimental compounds known as polyisoprene amide cysteine inhibitors (PCAIs). This approach differs from previous attempts because it does not target a specific mutation in the KRAS gene, but rather disrupts the protein interactions that various mutations rely on to continue stimulating cancer growth.
During experiments conducted on pancreatic cancer cells cultured in the laboratory, these compounds demonstrated a clear ability to slow the growth of cancer cells and limit their spread.
The compound NSL-YHJ-2-27 was the most effective among the compounds tested by the researchers, as it succeeded in reducing the migration of cancer cells by more than 90% even when used at low concentrations.
The analysis showed that these compounds work in several ways simultaneously; they enhance the activity of genes that inhibit tumor growth, reduce the activity of genes associated with cancer spread, and decrease the levels of proteins that help cancer cells move and invade neighboring tissues.
The compounds also disrupted actin filaments, a key part of the cell's internal structure, causing cancer cells to lose their ability to move and maintain their normal structure.
The researchers did not just test the compounds on conventional cells, but also tested them on three-dimensional models that simulate tumors in a more realistic way, where they again succeeded in stimulating the death of cancer cells and breaking down miniature tumors.
However, the study also revealed an unexpected result: the treatment overactivated certain cancer-related growth pathways instead of inhibiting them. Researchers believe this activation caused the cells to produce large amounts of reactive oxygen species, leading to their self-destruction, but the precise mechanism behind this phenomenon still requires further investigation.
The researchers stressed that these results are still preliminary, because the experiments have so far been limited to cells grown in the laboratory, which means that the compounds must first be tested on animals, and then their safety and effectiveness assessed in clinical trials before being used to treat patients.
These results are of particular importance because the impact of KRAS mutations is not limited to pancreatic cancer, but is associated with about 30% of solid tumors, including colorectal and lung cancers.
The team noted that the compounds showed efficacy against several different mutations in the KRAS gene, including KRAS-G12C, KRAS-G12D and KRAS-G12V, which enhances the possibility of developing a treatment that could be used against a wide range of cancers associated with this gene.
The study results were published in the journal Oncotarget.
