For ovarian and pancreatic cancer, early detection is challenging due to the lack of specific symptoms in the early stages. Surgery, radiation and chemotherapy are generally used to treat these cancer types. But many patients have poor prognosis, calling for the development of new therapeutics. Now a study appearing in The Journal of Clinical Investigation opens a door for new treatments for these devastating cancers. The researchers have created a molecule to target the the Gas6/Axl signaling pathway, which is involved in various types of human cancers.
The Axl receptor can bind and trap the Gas6 ligand with high affinity. This Gas6/Axl signaling pathway is a key driver of cancer metastasis and treatment resistance. Since both Gas6 and Axl play important roles in cancer, the Gas6/Axl axis is believed to be a promising target for cancer treatment. But one question is that GAS6 binds to AXL strongly.
A team of researchers from Stanford University School of Medicine have developed a decoy receptor, called MYD1-72, that binds to Gas6 better than Axl does. So the decoy receptor can inhibit Gas6 from binding to its native receptor Axl. Experiments in animal models of human cancers showed that MYD1-72 profoundly inhibited cancer progression.
Gas6 is a protein that binds to and activates the Axl receptor, which is important for cell survival, growth and migration. In many human cancers, including breast, lung and prostate cancer, Axl expression is upregulated and correlates with an advanced clinical stage. However, it is hard to target the Gas6/Axl axis because Axl binds to Gas6 very tightly.
The research team used the yeast display system to express different mutants of the Axl protein, and then used Gas6 tagged with a fluorescent molecule to identify the one with the highest affinity for Gas6. They eventually created MYD1-72, which binds to Gas6 much better than Axl does. They then tested the molecule in animal models of ovarian cancer and pancreatic cancer. Results showed that MYD1-72 prevented Gas6 from activating Axl, inhibited cell migration, and halted cancer growth. When MYD1-72 was used in combination with other chemotherapy drugs, the researchers found that the efficacy of MYD1-72 was enhanced. Amato J. Giaccia, who led the study, noted that MYD1-72 is effective in taking Gas6 out of the pathway.
The research hoped to move the experimental MYD1-72 into clinical use in humans. The molecule may also be used in other aggressive cancer types like blood cancer. Traditional cancer treatments including surgery, radiation and chemotherapy can reduce tumor but trigger side effects. What's worse, a lot of treated patients cannot remain in complete remission. For these reasons, many scientists are working to find alternative treatments. Antibiotics and small molecules are two types of promising cancer drugs. Co-author Rebecca Miao, PhD, noted that many treatments have toxicity, and that their new compound MYD1-72 appears to be effective and, even more importantly, safe. This is a big advantage of MYD1-72 over other drugs, and will facilitate the development of MYD1-72 as a cancer drug. Hence, clinical evaluation of MYD1-72 is justified, particularly when used in combination with standard chemotherapy, the researchers report.
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