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A groundbreaking study by researchers at the University of Michigan Rogel Cancer Center offers new hope for patients suffering from a particularly aggressive subtype of prostate cancer. In two studies published in Cell Reports Medicine, scientists have uncovered the mechanisms by which alterations in the CDK12 gene drive the disease, and they have developed a promising new treatment aimed at targeting and degrading this gene and its partner, CDK13.
Prostate cancer is one of the most common cancers in men, and while many cases are treatable, a small percentage of patients develop a more aggressive, treatment-resistant form. Approximately 7% of patients with metastatic prostate cancer have been found to have mutations in the CDK12 gene, according to DNA and RNA sequencing of tumor samples. This genetic alteration is also seen in some ovarian cancers, underscoring its significance across multiple cancer types.
Understanding CDK12’s Role in Cancer
To investigate how CDK12 loss promotes prostate cancer, the research team, led by Dr. Arul M. Chinnaiyan, M.D., Ph.D., developed a genetically engineered mouse model to mimic the genetic changes seen in human cancers. “What was quite surprising,” said Dr. Chinnaiyan, “was that CDK12 loss in the mouse prostate led to the formation of precursor lesions. When combined with the loss of the well-known oncogene p53, the mice developed invasive prostate cancer.”
This discovery represents a significant advance in prostate cancer research, as the mouse model closely mirrors the human condition. It provides an invaluable tool for further studying how CDK12 loss drives cancer development and offers a platform for testing new treatments.
The research team found that when CDK12 is lost, it leads to significant DNA damage within the cell. The loss of this gene causes the overexpression of other cancer-driving genes, and when combined with rapid DNA replication, this triggers a cascade of genetic instability, which drives the progression of the disease.
A Promising New Therapy
Building on their findings, the researchers turned their attention to developing a targeted treatment. Collaborating with Dr. Ke Ding, a medicinal chemist from the Shanghai Institute of Chemistry, the team created a degrader molecule that targets both CDK12 and CDK13. This new treatment approach works by binding to the proteins encoded by these genes, selectively destroying cancer cells while sparing normal cells.
In animal and cell line studies, the degrader showed remarkable potential. It successfully inhibited tumor growth and, crucially, could be administered orally—a significant breakthrough, as many protein-degrading therapies are too large to be absorbed in this way and require intravenous delivery.
A Synergistic Approach to Treatment
Interestingly, the study revealed that knocking down CDK12 and CDK13 activates the AKT pathway, a signaling pathway known to play a role in cancer development. This finding suggests a new therapeutic strategy: combining the CDK12/13 degrader with existing therapies that target the AKT pathway. Preclinical trials demonstrated a synergistic effect when these therapies were used together, offering hope that such a combination could be more effective than single-agent therapies.
“It’s well known that cancer patients often develop resistance to single therapies,” said Dr. Chinnaiyan. “By finding the right combination, such as the CDK12/13 degrader and AKT-targeting agents, we may be able to prevent resistance and improve treatment outcomes.”
Looking Ahead
While the research is still in its early stages, the development of the CDK12/13 degrader holds significant promise. The next step for the research team is to continue refining the degrader and advance it to clinical trials. If successful, this new therapy could offer a much-needed treatment option for patients with aggressive forms of prostate cancer.
This study not only underscores the importance of understanding genetic drivers of cancer but also highlights the power of international collaboration in drug development. The collaboration between researchers in Michigan and Shanghai has opened the door to a potentially transformative therapy that could benefit prostate cancer patients worldwide.
Conclusion
As prostate cancer continues to challenge the medical community, this new research provides hope for those affected by the more aggressive, treatment-resistant forms of the disease. By targeting the genetic alterations driving the cancer, researchers may soon offer a new avenue of treatment, improving outcomes and survival rates for many patients.
