They take a giant new step in the fight against the world’s most aggressive prostate cancer.

Prostate cancer has become the most diagnosed tumor in men in our country: more 33,750 new cases in 2023According to the Cancer Observatory of the Spanish Association Against Cancer. And projections show that this figure will continue to increase as it is expected that Eight out of ten men will develop this tumor during their lifetime. Therefore, early detection is important because if diagnosed early, the prognosis is very promising. cure rate exceeds 95%.

However, there are cases where the tumor is very aggressive and causes recurrence, so research to improve the prognosis in the most serious cases is still very much needed. Now the final discovery has been made University of Michigan Rogel Cancer Centerwhere a group of researchers first identified a new subtype of aggressive prostate cancer. In this scenario, they knew they needed to understand how this genetic change causes cancer and how to manage it with treatment.

Now, in two new papers published in the prestigious scientific journal Cell Reports Medicine, they do both: describe the mechanisms of how changes in the CDK12 gene lead to the development of prostate cancer, and report a promising disruptor that targets CDK12 and a related gene that kills tumors.

In particular, researchers previously discovered Loss of the CDK12 gene occurs in approximately 7% of patients with metastatic prostate cancer.suggesting that this change may be associated with a more aggressive form of the disease. This was discovered by sequencing the DNA and RNA of patient tumor samples. CDK12 also plays a role in the development of some types of ovarian cancer. To understand how loss of CDK12 affects cells at the molecular level, the researchers created mouse model to try to compare the genetic changes they observed in human prostate cancer.

Milestone

“What was quite surprising was that when we created loss of CDK12 in the mouse prostate, it led to the formation of lesion precursors in the mouse prostate. Then, when we added loss of the p53 oncogene, the mice developed a true invasive prostate cancer“, explains the main author, Arul M. ChinnayanM.D., director of the Michigan Translational Pathology Center and professor of pathology. “It will be an addition to this field to create a genetically modified mouse model similar to what we see in human prostate cancer,” he adds.

Using a mouse model, the researchers discovered mechanism by which loss of CDK12 causes DNA damage. In particular, the loss of this gene activates other known cancer-causing genes, causing them to be overexpressed at high levels and at the same time causing the DNA to replicate very quickly. The collision of these two processes causes DNA damage.

“These consistent studies taken together are quite impressive. We created an animal model and then deciphered the mechanisms by which loss of CDK12 actually causes prostate cancer,” Chinnaiyan details.

Promising therapy

The team also discovered that the associated gene, CDK13it is important to address the change therapeutically. They developed potential therapy designed to degrade CDK12 and CDK13. Tests in cell lines and mice showed that the degrader specifically binds to CDK12 and CDK13 and stops the growth of cancer cells on normal cells. In particular, the degrader can be absorbed orally and does not need to be administered intravenously. This is notable because most protein-degrading agents are too large to be absorbed orally, limiting their potential for drug development.

In addition, the researchers found that deletion of CDK12/13 activated the AKT pathway, which plays a role in cancer development. Combining a CDK12/13 degrader with existing ACT-targeted therapies resulted in synergistic effect in destroying cancer cells. This suggests the possibility of combining the CDK12/13 degrader with other approved therapies.

“It is well known that developing a single cancer treatment is challenging. Patients often develop resistance. If we can find the right combination, we could prevent resistance mechanisms from arising. This is one of the benefits of finding an FDA-approved agent to combine with CDK12/13 degraders,” admits Chinnaiyan.