Abstract PR006: PMR-116, a novel inhibitor of ribosome biogenesis with antitumor activity in preclinical models of prostate cancer

Advanced prostate cancer is characterised by mutations and amplifications of genes involved in regulating protein synthesis. PTEN-loss stimulates activity of the mTOR pathway, while amplification of MYC leads to increased ribosome biogenesis and elevated mRNA translation rate. Our previous work has demonstrated the efficacy of co-targeting ribosome biogenesis, via inhibition of RNA Pol I activity, and 4E-BP1 phosphorylation to suppress prostate cancer growth in vivo in GEMM of PCa and in patient-derived xenografts(1-3). In a collaboration with Pimera Inc., we investigated the efficacy of their new lead RNA Pol I inhibitor PMR-116 in models of prostate cancer. PMR-116 is well tolerated in vivo in mice and can be given at 300mg/kg weekly. Using the Hi-MYC mouse model of PCa we show that dosing 6-month-old mice once weekly for 4 weeks can decrease the incidence of invasive lesions by up to 85% compared to vehicle control while reverting glands to patterns of low grade intraepithelial neoplasia. PMR-116 rapidly inhibits proliferation in the Hi-MYC model with a 50% decrease in Ki67 observed 12 hours after oral administration. Conversely, PMR-116 showed minimal anti-tumour efficacy in the PTEN-null model of PCa suggesting that elevated MYC signalling may be required for optimal response. To further validate our promising GEMM results in more clinically relevant human-derived models, we used patient-derived xenografts lines we established from multidrug-resistant, metastatic PCa(4). PMR-116 treatment decreased tumour volume in all PDX tested including complete response in a line in which tumour volume decreased by ~90% compared to baseline. We believe this new RNA Pol I inhibitor shows promising results in a wide range of preclinical models of androgen receptor dependent and independent PCa and may exert higher efficacy in tumours expressing high levels of MYC. PMR-116 is currently in Phase I dose escalation trial in patient with solid tumours (ACTRN12620001146987). References: 1- Lawrence, MG et al. 2018. “Patient-Derived Models of Abiraterone- and Enzalutamide-Resistant Prostate Cancer Reveal Sensitivity to Ribosome-Directed Therapy.” European Urology 74 (5): 562–72. 2- Lawrence, MG. et al. 2021. “CX-5461 Sensitizes DNA Damage Repair-Proficient Castrate-Resistant Prostate Cancer to PARP Inhibition.” Molecular Cancer Therapeutics 20 (11): 2140–50. 3- Rebello, RJ. et al. 2016. “The Dual Inhibition of RNA Pol I Transcription and PIM Kinase as a New Therapeutic App