MENLO PARK, Calif., Oct. 28, 2015 /PRNewswire/ -- Two researchers from SRI Biosciences, a division of SRI International, were members of a team reporting in the journal Nature about a new way to target the gene underlying nearly a third of cancers. The article described research built upon work that Thomas R. Webb, Ph.D., director, Medicinal & Synthetic Chemistry, SRI Biosciences, has been doing for years: looking at a little-appreciated molecular machine called the spliceosome that is now gaining more recognition in scientific circles.
The spliceosome is a complex assembly of hundreds of proteins and RNA molecules. It takes RNA that is read from a living organism's DNA and then cuts and pastes—splices—it into various configurations while deleting unnecessary stretches. If this biological molecule is defective, proteins that ultimately result from its actions can be dysfunctional and lead to various forms of cancer.
In the recent findings published in Nature, a team of biologists led by researchers at Baylor College of Medicine used an antitumor drug developed by medicinal chemists Webb and Chandraiah Lagisetti, Ph.D., a senior scientist in Webb's lab, to show that cancers that rely on the gene MYC are dependent on the spliceosome for survival. MYC is frequently found in elevated amounts in cancers, including some of the most aggressive malignancies, such as breast, cervix and lung cancers.
The team found that this drug modulated the spliceosome and killed MYC-driven tumor cells without affecting normal cells, in mouse models. The compound designed by Webb's lab, sudemycin D6, targets the SF3B1 protein of the spliceosome.
The findings resulted from a meeting at a cancer conference in Washington, D.C., where Thomas (Trey) Westbrook, Ph.D., an associate professor from Baylor, and Webb came across each other's complementary work. In an "aha" moment, Westbrook and Webb realized their independent studies dovetailed.
Westbrook and colleagues had been using whole-genome genetic methods to identify genes that are required in Myc-driven cancers. With this approach, they identified many components of the spliceosome, of which SF3B1 is a key component. The two teams collaborated to show that genetic or pharmacologic inhibition of SF3B1 impairs both primary and metastatic growth of Myc-driven tumors.
"The genetic findings could only be translated to patients with a drug substance, which is why the discovery and development of SD6 is so important," said Webb. Sudemycin D6 was the piece of the puzzle that was put into place. Webb's team provided the drug, and they had already determined the safety and dosing regimen (published in the Journal of Medicinal Chemistry). "Once Westbrook used our drug and protocol, we were able to translate a genetic observation into a potential therapy," said Webb.
Because MYC has proven so difficult to target, the strategy of going after the spliceosome may prove to be a promising new tactic in cancer therapy.
"Thanks to the insights of numerous collaborators, our recent work may broadly impact both basic science and cancer treatment," said Webb, noting other 2015 publications of his group, including in Pharmacology Research & Perspectives. "My dream is that we develop the first successful splicing modulatory drug while paving the way for many other advances in the medicinal chemistry of cancer therapeutics and basic cancer biology."
This work was supported in part by NIH grant CA140474 and by the American Lebanese Syrian Associated Charities and St. Jude Children's Research Hospital.
Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under Award Number R01 CA 14047 4. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
About SRI Biosciences
SRI Biosciences, a division of SRI International, integrates basic biomedical research with drug and diagnostics discovery and preclinical and clinical development. SRI International, a research center headquartered in Menlo Park, California, creates world-changing solutions making people safer, healthier, and more productive.
SOURCE SRI International