A study published in Nature' recently has revealed that a molecule isolated from sea sponges and then synthesized in lab can curtail the growth of leukemia cancer cells. The team of researchers consisted of scientists from Harvard and is led by Professor of Chemistry and Chemical Biology Matthew Shair. The results are encouraging and can open the door to a new treatment for leukemia.
Shair said that once they found that the molecule named cortistatin A was quite potent and selective in inhibiting the growth of AML cells, they tested it in mouse models of AML. The results are quite positive; cortistatin A is quite as efficacious without any undesirable effects. What the researchers have identified seems like a very promising new therapeutic approach.
Cortistatin A was synthesized by the researchers and they are now working to develop novel therapeutics based on it by optimizing its drug-like properties. Since, there is a dearth of effective treatments for AML; the importance of advancing it toward clinical trials soon is tremendous. Typically, it takes years to develop drugs, but Shair's lab is very close to having a development candidate that could be taken into late-stage preclinical development and then into clinical trials. What they will need is an industrial partner to progress the technology along that path and toward eventual regulatory approval. The good news is that Harvard’s Office of Technology Development (OTD) is engaged in advanced discussions for that.
Cortistatin A works by inhibiting a pair of nearly identical kinases, called CDK8 and CDK19, which as per Shair's work play a key role in the growth of AML cells. It is seen that the kinases operate as part of a poorly understood, massive structure in the nucleus of cells called the mediator complex, which acts as a bridge between transcription factors and transcriptional machinery. When these two specific kinases were inhibited, Shair and fellow researchers found that it doesn’t shut down all transcription, but has gene-specific effects.
Shair explained that they treated AML cells with cortistatin A and then measured the effects on gene expression. Surprisingly, they found that it affects a very small number of genes a number that was expected in thousands but it runs in the low hundreds. Upon further study, it was found that the genes that were affected were associated with DNA regulatory elements known as “super-enhancers.” These super-enhancers drive high expression of genes, many of which dictate cellular identity. When cancer happens identity is lost, and the cells become poorly differentiated and are stuck in an almost stem-cell-like state. Some potential cancer treatments attack the disease by down-regulating such cellular identity genes, but to Shair and colleagues' surprise, it is seen that their molecule actually turned up the activity of those genes in AML cells.
400 kinases were tested upon and it was found that Cortistatin inhibits only CDK8 and CDK19 in cells, making it among the most selective kinase inhibitors identified till now. Shair said that to have compounds that precisely hit a specific target, like cortistatin A can help reduce side-effects and increase efficacy. This molecule does it because of its three-dimensional structure. One way to achieve this level of specificity is to make molecules more like cortistatin A.
Since Shair’s team synthesized the molecule; they could study how it worked and why it affected the growth of a very specific type of cell. With funds and drug-development expertise provided by Harvard’s Blavatnik Biomedical Accelerator, they also created a range of new molecules that may be better suited to clinical application. There are 32 chemical steps involved in the complex process of making cortistatin A, but they have found less complex structures that act just like the natural compound, with better drug-like properties. Also, they can be manufactured on a large scale and in about half the steps.
While there is still much research to be donethe early results are quite dramatic. Shair said that he was quite excited and curious to see where this research leads them,