Molecule Inhibits Kinase Pair, Leading to Restored Normal Cell Function in Cancerous Cells

A molecule isolated from sea sponges and later synthesized can halt the growth of cancerous cells, opening the door to a new treatment for leukemia. The finding was described in the journal Nature (2015; doi:10.1038/nature14904).

"Once we learned this molecule, named cortistatin A, was very potent and selective in terms of inhibiting the growth of AML cells, we tested it in mouse models of AML and found that it was as efficacious as any other molecule we had seen, without having deleterious effects," said Matthew Shair, PhD, professor of Chemistry and Chemical Biology at Harvard University in Cambridge, Massachusetts. "This suggests we have identified a promising new therapeutic approach." And, it could be available to test in patients relatively soon.

"We synthesized cortistatin A, and we are working to develop novel therapeutics based on it by optimizing its drug-like properties," Shair said. "Given the dearth of effective treatments for AML, we recognize the importance of advancing it toward clinical trials as quickly as possible."

The drug development process takes years, but Shair's lab is very close to having what is known as a development candidate that could be taken into late-stage preclinical development and then into clinical trials. An industrial partner will be needed to progress the technology along that path and toward eventual regulatory approval.

The molecule works, Shair explained, by inhibiting CDK8 and CDK19, a pair of nearly identical kinases that his work indicates play a key role in the growth of AML cells.

The kinases operate as part of the mediator complex, a poorly understood, massive structure in the nucleus of cells that acts as a bridge between transcription factors and transcriptional machinery. The researchers found that inhibiting these two specific kinases does not shut down all transcription, but instead has gene-specific effects.

"We treated AML cells with cortistatin A and measured the effects on gene expression," Shair said. "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."

"Humans have about 220 different types of cells in their body: they all have the same genome, but they have to form things like skin and bone and liver cells," Shair explained. "In all cells, there are a relatively small number of DNA regulatory elements, called super-enhancers. These super-enhancers drive high expression of genes, many of which dictate cellular identity. A big part of cancer is a situation where that identity is lost, and the cells become poorly differentiated and are stuck in an almost stem-cell-like state."

A few promising potential cancer treatments have attacked the disease by down-regulating such cellular identity genes, but Shair and colleagues were surprised to find that their molecule actually turned up the activity of those genes in AML cells.

"Before this paper, the thought was that cancer is ramping these genes up, keeping the cells in a hyper-proliferative state, and affecting cell growth in that way," Shair said. "But our molecule is saying that's one part of the story, and in addition cancer is keeping the dosage of these genes in a narrow range. If it's too low, the cells die. If they are pushed too high, as with cortistatin A, they return to their normal identity and stop growing."

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