Researchers at the University of Michigan Rogel Cancer Center have recently uncovered a novel subtype of aggressive prostate cancer. Recognizing the significance of this discovery, they set out to investigate the underlying genetic mechanisms driving this cancer subtype and explore potential targeted therapeutic approaches.
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In two newly published studies in Cell Reports Medicine, the researchers have elucidated the role of alterations in the CDK12 gene in the development of prostate cancer. They have also reported on a promising degrader compound that targets CDK12 and a related gene to effectively eliminate tumor cells.
Previous studies had identified the loss of the CDK12 gene in approximately 7 % of patients with metastatic prostate cancer, suggesting a potential link between this genetic alteration and a more aggressive form of the disease. This finding was based on comprehensive DNA and RNA sequencing analyses of patient-derived tumor samples. Interestingly, CDK12 has also been implicated in certain ovarian cancer cases.
To investigate the molecular-level effects of CDK12 deficiency, researchers developed a mouse model that mimics the genetic changes observed in human prostate cancer cases.
What was quite surprising was when we created CDK12 loss in a mouse prostate, this caused precursor lesions to form in the mouse prostate. Then, when we added loss of the p53 oncogene, the mice developed bona fide invasive prostate cancer. It will be an addition to the field to have a genetically engineered mouse model that parallels what we see in human prostate cancer.”
Arul M. Chinnaiyan, Study Senior Author and Director, Center for Translational Pathology, University of Michigan
Arul is also an S.P. Hicks Professor of Pathology at Michigan Medicine.
In the mouse model, researchers have uncovered the underlying mechanism by which the loss of CDK12 triggers DNA damage. The absence of this gene leads to the activation and overexpression of other well-established cancer-driving genes. This, in turn, results in an accelerated rate of DNA replication. The collision between these two concurrent processes ultimately culminates in DNA damage.
“These back-to-back studies taken together are quite impressive. We created an animal model and then deciphered the mechanisms of how CDK12 loss drives prostate cancer,” Chinnaiyan said.
The research team has identified a partner gene, CDK13, as a crucial target for therapeutic intervention. They have developed a potential therapy designed to degrade both CDK12 and CDK13.
Extensive testing in cell lines and animal models has demonstrated that this degrader specifically binds to CDK12 and CDK13, effectively halting the growth of cancer cells while sparing normal cells.
Notably, this degrader can be administered orally, which is a significant advantage over many protein degraders that are too large to be absorbed through the digestive system, limiting their potential in drug development.
Furthermore, the researchers found that knocking down CDK12/13 activates the AKT pathway, a key player in cancer development.
Combining the CDK12/13 degrader with existing therapies targeting the AKT pathway showed a synergistic effect in destroying cancer cells. This finding suggests the potential to combine a CDK12/13 degrader with other approved therapies, expanding the therapeutic options for cancer treatment.
It is well known that single therapies for cancer treatment have been challenging. Oftentimes patients develop resistance. If we can find the right combination, we could prevent resistance mechanisms from occurring. That is one of the benefits of finding an FDA-approved agent to combine with CDK12/13 degraders. This study also highlights an international collaboration with Ke Ding, Ph.D., a medicinal chemist at the Shanghai Institute of Chemistry, in the development of orally bioavailable CDK12/13 degraders.”
Arul M. Chinnaiyan, Study Senior Author and Director, Center for Translational Pathology, University of Michigan
Investigators intend to continue enhancing the CDK12/13 degrader to progress it toward a clinical evaluation phase. The team aims to refine and optimize the degrader compound to initiate a clinical trial to assess its safety and efficacy in a patient population.
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Journal reference:
Tien, J. et al. (2024) CDK12 loss drives prostate cancer progression, transcription-replication conflicts, and synthetic lethality with paralog CDK13. Cell Reports Medicine. doi.org/10.1016/j.xcrm.2024.101758.