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Breakthrough in Aggressive Prostate Cancer Treatment Unveiled
A groundbreaking discovery from researchers at the University of Michigan Rogel Cancer Center has unveiled a new aggressive subtype of prostate cancer linked to specific genetic changes. The team aimed to dissect the mechanisms behind this alteration and explore treatment avenues targeting it.
Two recent studies published in Cell Reports Medicine delve into the intricacies of the CDK12 gene, revealing how its alterations contribute to the progression of prostate cancer. The findings encompass not only the biological pathways involved but also a promising therapeutic approach that targets both CDK12 and a related gene to combat tumor growth.
Prior research indicated that nearly 7% of patients with metastatic prostate cancer exhibit a loss of the CDK12 gene, a finding derived from comprehensive DNA and RNA sequencing of tumor samples. This genetic alteration suggests a correlation with a more aggressive cancer form, and CDK12 is also implicated in certain ovarian cancers.
To investigate the molecular consequences of CDK12 loss, the researchers developed a mouse model reflecting the genetic changes observed in human cases. This innovative approach shed light on the relationship between CDK12 loss and cancer progression.
Senior author Arul M. Chinnaiyan, M.D., Ph.D., emphasized the significance of their findings: “When we simulated CDK12 loss in mouse prostate tissue, we observed the development of precursor lesions. The additional loss of the p53 oncogene led these mice to develop invasive prostate cancer. This genetically engineered mouse model is a significant addition to our understanding of human prostate cancer,” he stated.
Utilizing the mouse model, the team uncovered the mechanism by which CDK12 loss leads to DNA damage. They found that the absence of this gene triggers the overexpression of other cancer-associated genes and results in unusually rapid DNA replication, culminating in DNA damage due to the interplay between these accelerated processes.
Chinnaiyan remarked on the dual nature of their studies: “Together, these studies are quite impressive as they established a model and elucidated how CDK12 loss drives prostate cancer.” This research marks a significant leap in understanding the complexities of prostate cancer at a molecular level.
Additionally, the researchers identified that the CDK13 gene works in concert with CDK12, providing another layer for therapeutic targeting. They successfully formulated a new compound designed to degrade both CDK12 and CDK13. Initial tests on cell lines and mice demonstrated that this degrader effectively binds to its targets and inhibits cancer cell proliferation while sparing normal cells. Remarkably, this degrader can be administered orally, diverging from the typical intravenous routes required for many protein degraders, which tend to be too large for oral absorption.
Moreover, the study revealed that downregulation of CDK12 and CDK13 activates the AKT signaling pathway, which is known to contribute to cancer development. The researchers observed that combining the CDK12/13 degrader with existing AKT inhibitors resulted in a synergistic effect, enhancing the destruction of cancer cells. This opens the door for potentially effective combination therapies using FDA-approved medications alongside the novel degrader.
“It’s widely recognized that monotherapies in cancer treatment often face challenges such as patient resistance,” Chinnaiyan noted. “By exploring effective combinations, we can potentially mitigate resistance mechanisms. This study also showcases an international collaboration with Ke Ding, Ph.D., from the Shanghai Institute of Chemistry, contributing to the creation of these orally bioavailable CDK12/13 degraders.”
Looking ahead, the research team intends to advance the development of the CDK12/13 degrader, with aspirations of initiating clinical trials in the near future.
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