On Oct. 29, 2024, the Journal of Experimental Medicine published a study co-authored by Director of Prostate Cancer Research Hui-Kuan “Kevin” Lin, PhD, Johnston-West Endowed Chair of Pathology Jiaoti Huang, MD, PhD, and Assistant Professor of Pathology Che-Chia Hsu, PhD titled “IMPA1-Derived Inositol Maintains Stemness in Castration-Resistant Prostate Cancer Via IMPDH2 Activation.” Duke Professor of Medicine Andrew J. Armstrong, MD, was also an author.
The study offers a mechanistic understanding of how prostate cancer progresses from androgen-sensitive prostate cancer to castration-resistant prostate cancer (CRPC). It shows that inositol derived from the enzyme inositol monophosphatase 1 (IMPA1) is a key mechanism that drives the CRPC progression and androgen ablation therapy (ABT) resistance through activating Inosine Monophosphate Dehydrogenase 2 (IMPDH2). It identifies inositol as a signaling metabolite directly activating IMPDH2 to drive these processes and offers a new paradigm and strategy to target CRPC and overcome ABT resistance.
By identifying a metabolic vulnerability of cancer, the study significantly advances the current understanding of how CRPC is regulated and explains the molecular basis underlying prostate cancer stem cell (PCSC) maintenance.
There are many possible implications for patient care:
- The study offers a combination therapy for targeting castration-resistant prostate cancer.
- Targeting of IMPA1/inositol/IMPDH2 axis through either IMPA1 or IMPDH2 inhibition represents a promising strategy for targeting CRPC and overcoming ABT resistance.
- It identifies inositol as a potential serum marker beside prostate-specific antigen (PSA) that can be used to monitor prostate cancer initiation, progression, and treatment response for CRPC.
- The IMPA1 gene amplification and upregulation serves as a potential biomarker for prostate cancer progression and represents poor survival outcome for prostate cancer patients.