Promising drug compounds target liver cancer
Singaporean scientists have discovered four potential drug compounds that target hepatocellular carcinoma (HCC), the most common type of liver cancer. Their findings, made using a cancer gene-targeting drug-screening platform and published in the journal Gastroenterology, are expected to pave the way for new and more effective treatments for liver cancer as well as other cancers.
Liver cancer is the sixth most common cancer worldwide and the second-leading cause of cancer death worldwide, affecting about 24 individuals in every 100,000 people a year. HCC accounts for 85% of liver cancer occurrence and is lacking in effective therapeutic interventions; current drugs used to treat HCC are not durable, and are typically only used to treat patients with advanced-stage disease. Advances in therapeutic discovery for HCC are thus required.
With this in mind, scientists from the National University of Singapore (NUS) and the Agency for Science, Technology and Research (A*STAR), collaborating with Brigham and Women’s Hospital and the Harvard Medical School, set out to develop a cancer gene-targeting drug-screening platform that tapped on libraries of synthetic molecules and natural compounds to identify potential drug candidates against SALL4 — a protein that is expressed in 30–50% of HCC tumours. The theory was that these natural compounds could potentially limit SALL4-linked HCC cancer cell growth.
A probe into these compounds revealed that they are inhibitors of oxidative phosphorylation, a metabolic pathway that promotes the growth of cancer cells with high SALL4 expression. The team further demonstrated that the most potent natural compound identified, oligomycin, had a higher efficacy than existing standard-of-care drug sorafenib in preclinical studies, and displayed little toxicity at effective doses.
Oligomycin is produced by streptomyces bacteria and, when combined with sorafenib, could further reduce the growth of SALL4-linked HCC tumours in vivo. Oligomycin may also be used to suppress other SALL4-linked cancers, such as lung cancer. Furthermore, the findings collectively suggest that SALL4 serves as a potential biomarker for clinicians to select cancer patients who could benefit from therapies involving oxidative phosphorylation inhibitors that disrupt the metabolism of certain tumour types.
“Our study has identified a vulnerability in tumours that express cancer gene SALL4, as well as compounds targeting this vulnerability,” said study leader Dr Justin Tan, from NUS and A*STAR. “These compounds have great potential to be further developed into drugs to effectively treat liver cancer and other cancers linked to this gene. Further studies on these compounds can lend deeper insights to bring advancement to precision medicine for SALL4-linked cancers, and to improve the quality of cancer treatments.”
Moving forward, the team plans to further develop the oxidative phosphorylation inhibitors discovered for clinical testing in cancer patients, with the hope of bringing a more effective treatment option to patients with SALL4-linked cancers. The team also aims to expand their innovative drug-screening platform to discover drugs that target other cancer genes in different cancer types.
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