Liver cancer is the second leading cause of cancer-related deaths worldwide. The most common primary liver cancer in adults is known as hepatocellular carcinoma (HCC), and accounts for approximately 780,000 deaths every year. Even with advanced surgical treatments or transplantation, the 5-year survival rate for HCC patients remains poor due to frequent recurrence.
Now, researchers have demonstrated a potential method for treating advanced liver cancers like HCC. Led by Associate Professor Edward Chow and Dr Tan Boon Toh, a team of scientists showed that a class of small molecule drugs that target the JAK/STAT signaling pathway could be used to fight against the disease.
“Targeting molecular mechanisms that drive chemoresistance has shown success in clinical trials for other diseases. Therefore, such targeted approaches can be potentially useful as adjuvant therapies to improve clinical outcomes of HCC patients,” explained Chow.
Inhibiting the JAK/STAT signaling pathway
The JAK/STAT signaling pathway is an important set of proteins that control a wide range of biological functions, including immune responses and cellular development. This pathway typically responds to external cellular cues to turn on specific sets of genes that help cells properly develop or allow the immune system to fight off infections. As such, if the JAK/STAT signaling pathway somehow goes awry, it can lead to the formation of tumors.
In their study, the NUS team targeted the JAK/STAT pathway to inhibit its action in tumor formation. They showed that a subpopulation of cancer ‘stem-like’ cells are sensitive to a class of small molecule drugs that inhibit the JAK/STAT pathway. These stem-like cells can self-renew and are responsible for causing the cancer cells that comprise the tumor.
Toh, co-lead author of the study, explained the significance of these findings, “We can now potentially use small molecule compounds to target these specific small population of cancer stem-like cells that are often the cause of tumor recurrence.”
Small molecule drug candidates effective in reducing cancer progression
The researchers were able to isolate these tumor-initiating cancer cells that are often the culprits of therapy resistance that leads to cancer relapse. They found that an important cancer pathway, known as the JAK/STAT signaling pathway, was enriched in this cancer stem-like population of cells.
In this study, JAK/STAT inhibitors targeting cancer stem-like cells were able to effectively reduce cancer progression in preclinical models of liver cancer. The NUS team found that the tumor-forming ability was reduced by 50 percent after drug treatment.
Lim Jhin Jieh, co-first author of the paper, said, “This study highlights a novel strategy in treating liver cancer patients whose tumors show aberrant activity of important cellular pathways. Blocking the activity of an alternative pathway with small molecule drugs could effectively eradicate the cancer at its roots and prevent a relapse.”
These findings provide increased support that JAK/STAT-based therapies targeting cancer stem-like cells are important for more effective treatment outcomes against liver cancer.
Chow said, “The immediate next step is to validate this concept in our collection of clinically relevant patient-derived tumor xenografts and organoids.” JAK/STAT inhibitors are also now being tested in clinical trials for the treatment of other solid cancers.
Toh et al. (2019). Targeting Jak/Stat pathway as a therapeutic strategy against SP/CD44+ tumorigenic cells in Akt/β-catenin-driven hepatocellular carcinoma. Journal of Hepatology. DOI: https://doi.org/10.1016/j.jhep.2019.08.035
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