Data from a team of Australian researchers shows the potential of a new therapeutic strategy for treating castration-resistant prostate cancer (CRPC), the most aggressive form of the disease. The research, published in the British Journal of Cancer, studied the role of Cyclin-Dependent Kinase 9 (CDK9) in the progression of aggressive prostate cancer and tested whether the CDK9 inhibitor CDKI-73 has the potential to overcome CRPC treatment resistance.
The research reveals that CDK9 plays a crucial role in promoting the growth and survival of prostate cancer cells. “CDK9 expression is associated with tumor grade and is predictive of disease recurrence following surgery. Importantly, CDK9 expression is highest in CRPC, including AR-low/independent NEPC (neuroendocrine prostate cancer) tumors. Mechanistically, this can be explained at least in part by the increased copy number of the CDK9 gene, which is particularly evident in NEPC.”
In their study, the researchers investigated CDKI-73, an orally deliverable CDK9 inhibitor, to assess its effectiveness in treating prostate cancer. Previous pre-clinical investigations of CDKI-73 has shown its anti-tumor activity against acute myeloid leukemia, ovarian cancer, colorectal cancer, and melanoma. It is currently being tested in a Phase II clinical trial in patients with relapsed and therapy resistant acute myeloid leukemia (AML).
Their research was conducted on an array of prostate cancer models including cell lines, xenografts, primary tumors in explant culture systems, and organoids derived from men with CRPC.
“Our research demonstrates that CDKI-73 potently blocks the growth of prostate cancer, even aggressive subtypes of the disease that are resistant to current treatments,” said Luke Selth, PhD, an associate professor at Flinders University who co-led the study. “Importantly, CDKI-73 targets cancer cells specifically without harming normal cells and its potential as an oral capsule makes it an attractive treatment option.”
The study also noted that CDKI-73 showed minimal toxicity in mouse models and has favorable oral bioavailability, which could hasten its potential use in the clinic.
In addition, the team investigated the use of CDKI-73 as part of a combination therapy. Specifically, it showed that the combination of CDKI-73 and the BRD4 inhibitor AZD5153, showed significant promise in preclinical prostate cancer models. “This combination strategy could enhance therapeutic efficacy, given that CDK9 and BRD4 play complementary roles in amplifying oncogenic gene expression programs,” they wrote.
While their findings show promise, the team noted a few important limitations of their study. Most notable was that while CDKI-73 is highly selective for CDK9, it also inhibits other CDKs at lower concentrations, which may contribute to its effects. The investigators wrote, “Inhibition of CDK9 is the major mechanism by which CDKI-73 exerts anti-tumor activity in prostate cancer,” suggesting that further research is needed to fully understand its mechanisms and optimize its use in clinical settings.
Co-leader of the study professor Shudong Wang, PhD, from the University of South Australia, who developed CDKI-73, added: “This study demonstrates that CDKI-73 is a promising candidate for treating solid tumors such as prostate cancer. Our proof-of-principle study is an important step towards future clinical trials and these findings will inform future studies in the use and efficacy of CDKI-73 as a prostate cancer treatment.”
