New Discovery May Improve Use of Radiation and ADT in Men With Prostate Cancer

Investigators at the University of Virginia (UVA) Health System are now reporting that there is a common connection between the use radiation and androgen deprivation therapy.

Investigators at the University of Virginia (UVA) Health System are now reporting that there is a common connection between the use radiation and androgen deprivation therapy.  It is a connection that may be manipulated in a way that could allow for both treatments to be more effective in men with castration-resistant prostate cancer (CRPC).

The new findings, which have just been published online in the journal Cancer Research, suggest that manipulating the signaling pathway checkpoint kinase 2 (CHK2) may improve outcomes in men with CRPC. They propose that CHK2 is a negative regulator of androgen sensitivity and prostate cancer growth, and theorize CHK2 signaling is lost during prostate cancer progression to castration resistance.

“Now we have a novel link between two different standards of care for advanced prostate cancer,” said UVA researcher Dan Gioeli, PhD, Department of Microbiology, Immunology and Cancer Biology, Charlottesville, Va, in a news release. “For locally advanced prostate cancer, radiation therapy is one of the standards of care, and that induces DNA damage, which would activate this pathway. Another standard of care for metastatic prostate cancer is androgen ablation, and that acts to inhibit androgen receptor activity. Now we have a new molecular understanding of how those two different standards of care might be connected.”

Drugs that could capitalize on the discovery are already in the pipeline and major pharmaceutical compares are already developing agents that inhibit CHK kinases. Gioeli said a clinical trial to test whether the finding could improve treatments for prostate cancer patients could begin in the not too distant future.  

Gioeli and his team believe these new findings now may allow clinicians to better determine which forms of treatment will most benefit individual patients. In addition, the findings have implications for treating other forms of cancer, not just prostate cancer.

“The next steps are to see whether our predictions about … targeting this pathway could enhance cancer-killing in response to radiation or androgen ablation,” explained Gioeli. “Perhaps it would lead to a three-way combination where we would be looking at how androgen withdrawal sensitizes tumor cells to radiation therapy and whether we can further enhance that sensitization by inhibiting this pathway.”

The researchers noted that curing metastatic disease remains a significant challenge and almost all men with disseminated prostate cancer initially respond to androgen deprivation therapy (ADT), but virtually all patients will relapse and develop CRPC. 

The researchers discovered through a high-throughput RNAi screen that CHK2 knockdown dramatically increased prostate cancer growth and hypersensitized cells to low androgen levels. Further, they found the effects of CHK2 were dependent on the downstream signaling proteins CDC25C and CDK1.

With this new information, doctors may be able to alter the signaling pathway, CHK2, to make it easier to kill prostate cancer cells.