A research team led by scientists at The Scripps Research Institute (TSRI) Florida campus has identified a novel approach to treating prostate cancer that involves blocking a newly discovered, constitutively active signaling circuit that plays a role in the development of androgen therapy resistance and aggressive tumor growth. Studies by TSRI associate professor Jun-Li Luo, Ph.D., M.D., and colleagues have found that inhibiting components in this circuit can hold back the progression of therapy-resistant advanced prostate cancer.

Androgen therapy is the most effective treatment for advanced prostate cancer, but nearly all patients will eventually develop resistance. The signaling circuit identified by Dr. Luo and colleagues comprises the protein complex IκBα/NF-κB (p65), miR-196b-3p, Meis2, and PPP3CC, and controls the expression of stem cell transcription factors that drive tumorigenicity. Being constitutively active, the circuit “is not dependent on the activation of other traditional IKKβ/NF-κB pathways that are important in normal immune responses,” the authors write in their paper “A Constitutive Intrinsic Inflammatory Signaling Circuit Composed of miR-196b, Meis2, PPP3CC, and p65 Drives Prostate Cancer Castration Resistance,” published in Molecular Cell. This “opens the door for potential treatment options,” Dr. Luo comments.

NF-κB is a key target for cancer therapy, but NF-κB inhibitors can also cause severe side effects related to immunosuppression that results from the unwanted inhibition of NF-κB in normal immune cells. The TSRI research indicates that targeting the non-IκBα/NF-κB components in the newly discovered signaling circuit would avoid the suppression of NF-κB in normal immune system cells, without affecting anticancer potency.

“Disrupting this circuit by targeting any of its individual components blocks the expression of these transcription factors and significantly impairs therapy-resistant prostate cancer,” suggests TSRI research associate Ji-Hak Jeong, the first author of the study. “Our studies present deep insight into the bona fide mechanisms underlying castration resistance and provide the foundation for the development of CRPC [castration-resistance prostate cancer] therapeutic strategies that would be highly efficient while avoiding indiscriminate IKK/NF-κB inhibition in normal cells,” the authors conclude.


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