Matthew Shair, a professor of chemistry and chemical biology at Harvard, and his team have isolated and synthesized a molecule from sea sponges that prevents cancerous growth.
These findings have direct implications to leukemia patients and could one day provide a new treatment for those faced with an altered life expectancy from this malignant disease. The paper was published this month in Nature.
"Once we learned this molecule named cortistatin A was very potent and selective in terms of inhibiting the growth of AML [acute myeloid leukemia] cells, we tested it in mouse models of AML and found that it was as efficacious as any other molecule we had seen, without deleterious effects," Shair said in a release. "This suggests we have identified a promising new therapeutic approach."
Cortistatin A was isolated from sea sponges and since synthesizing it in their lab the researchers found it works by inhibiting a pair of enzymes--called CDK8 and CDK19--both critical to the growth of AML cells.
They went deeper into the cancerous cells to discover that the kinases operate as a massive structure in the nucleus, called mediator complexes. When inhibited, these link transcription factors and transcriptional proteins have gene-specific effects which halt cancer growth.
"We treated AML cells with cortistatin A and measured the effects on gene expression," Shair said in the release. "One of the first surprises was that it's affecting a very small number of genes--we thought it might be in the thousands, but it's in the low hundreds."
Shair, senior research associate Henry Pelish, and his then-PhD student Brian Liau further associated these differentially expressed genes with areas of DNA regulatory elements called "superenhancers"--which drive higher than normal expression of genes and genes crucial for cell identity, which is lost in AML cells.
Cortistatin A seems to work by upregulating these important genes which can reach a level of expression that inhibits growth of AML cells and they revert to their normal cell type.
After testing 400 kinases they found that CDK8 and CDK19 are the only kinases inhibited, which gives remarkable specificity for a kinase inhibitor. Specificity reduces the number of off-target effects.
They plan to enter late-stage preclinical trials soon for their development candidate, and their hopes remain high for clinical trials soon after.
- here's the release
- get the research abstract