According to a recent study done at Harvard University, and published in the journal Nature, a molecule gleaned from sea sponges – cortistatin A – can stop cancerous cells from multiplying and could be potentially used for the treatment of leukaemia.
Leukaemia is the most common cancer in children and teens, accounting for almost 1 out of 3 cancers. The most prevalent childhood leukaemias are Acute Lymphocytic Leukaemia (ALL) and Acute Myeloid Leukaemia (AML). Chronic leukaemias are very rare in children.
The study was led by Henry Pelish, Senior Research Associate in Chemistry and Chemical Biology, and Matthew Shair, Professor of Chemistry and Chemical Biology.
During the research, results of tests on mouse models of AML showed that the compound stunted the growth of tumour cells without causing any harmful side effects. Cortistatin A apparently affects the growth of AML cells by inhibiting two enzymes CDK8 and CDK19 that are a part of the mediator complex in the nucleus.
In order to make this post more easily understandable to those of us not in the scientific or medical professions, I will try to explain the results in plain English….
“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.”
The mediator complex is basically a multi-protein complex that has emerged as a master coordinator of development and cell lineage determination. In other words, it controls DNA functions that determine how certain cells develop.
Mediator functions include involvement in developmental abnormalities, cancer and metabolic disorders. In other words, the Mediator acts as a master coordinator that regulates various aspects of transcription both during development and in adults.
Transcription is basically the organic process whereby the DNA sequence in a gene is copied into mRNA (click to enlarge pic below to read easily)
During the research it was discovered that treating AML cells with cortistatin A affects only a small number of genes, several of which were associated with DNA-regulatory elements known as “super-enhancers” which is good news because it means that cortistatin A is among the most selective kinase inhibitors identified to date.
It was discovered that cancer cortistatin A induced the activity of these genes in AML cells (as opposed to other potential anti-cancer molecules which are known to down-regulate these genes), which is a good thing because….
Prior to this study, it was thought that cancer is ramping these genes up, keeping the cells in a state of rapid multiplication and affecting cell growth in that way, but cortistatin A has actually shown that is only part of the story; normally 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.”
Cortistatin A was tested on approximately 400 kinases, and it was found that it inhibits only CDK8 and CDK19 in cells. This is thought to be because it has a three-dimensional structure (most kinase inhibitor drugs do not have this type of three-dimensional structure); this means that it can precisely hit a specific target, and this can help reduce side-effects and increase efficacy.
Cortistatin A was initially isolated from sea sponges, and later synthesised in Shair’s laboratory. It is a complex molecule and the team is working on synthesising less complex and more drug-like derivatives of cortistatin A in order to make it more feasible to produce the compound on a large scale.
Shair’s lab has created a range of new molecules that may be better suited to clinical application and which will be screened for their activity, tested in pre-clinical studies in animals and then followed by trials in human subjects.
While further research and various clinical trials still need to take place, this is an important milestone that affords these scientists an opportunity to generate a new understanding of cancer and develop new therapeutics to treat it.