When the team at the University of Michigan Rogel Cancer Centre discovered a new, aggressive variant of the prostate cancer gene mutation, they quickly knew that they needed to understand how this particular gene mutation was encouraging the cancer and how it could be stopped.
In two newspapers, both published in Cell Reports Medicine, they do both, explaining how alterations in the CDK12 gene lead to prostate cancer and proposing a degrader that targets both CDK12 and another gene to get rid of tumours. They confirmed this from the whole genome and transcriptome analysis of the tumor tissue of the patients.
CDK12 is also involved in some ovarian cancers. To gain insight into the molecular consequences of CDK12 loss in cells, the authors developed a mouse model that recapitulated the genetic alterations that the investigators were noticing in human prostate cancer.
The most surprising result was that when we deleted CDK12 in the mouse prostate this resulted in the formation of precursor lesions in mouse prostate cancer. Afterward, when they removed the p53 tumour suppressor gene, the mice developed what can be called “real prostate cancer,” said Dr. Arul M. Chinnaiyan of the University of Michigan, the first author of the study.
The team also identified the partner gene CDK13 as being essential for the treatment of the alteration in question. They designed a possible treatment strategy for the removal of CDK12 and CDK13.
Murine and cell culture tests showed that the degrader specifically binds to CDK12 and CDK13 and inhibits the growth of cancer cells but not normal cells. The degrader can be administered orally and does not have to be injected into the patient’s vein.
This is important because most protein degraders cannot be transported via the digestive system as they are relatively large molecules and this has been a major limitation in their application in drug development.
Furthermore, they argue that silencing CDK12/13 leads to activation of AKT signalling which is implicated in carcinogenesis. This combination with CDK12/13 degrader and AKT inhibitors enhanced the effectiveness of cancer cell elimination.
This provides an opportunity to use a CDK12/13 degrader with other therapies that have already been developed and are available in the market.
This is because the single agent therapies have not been very effective for cancer treatment. This is the case most of the times because the patients develop resistance.
If we can find a right middle ground then we will not have to worry about resistance mechanisms. This is because many times the patients become resistant. If we can identify the right balance, we could avoid the development of resistance mechanisms.
That is one of the advantages of identifying a compound which is FDA approved to be used in combination with CDK12/13 degraders,” Chinnaiyan added. “
Reference:Â University of Michigan. Research points to potential new treatment for aggressive prostate cancer subtype
