Abstract PR006: PMR-116, a novel inhibitor of ribosome biogenesis with antitumor activity in preclinical models of prostate cancer
Authors: Huglo Alisee , Hedwards Shelley , Lawrence Mitchell , Rebello Richard , Clark Ashlee , Risbridger Gail , Taylor Renea , Drygin Denis , Haddach Mustapha , Hannan Katherine M. , Hannan Ross D. , Furic Luc 
Published: June 2023

Abstract
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 Approach to Treat Advanced Prostate Cancer.” Clinical Cancer Research 22 (22): 5539–52. 4- Risbridger, GP et al. 2021. “The MURAL Collection of Prostate Cancer Patient-Derived Xenografts Enables Discovery through Preclinical Models of Uro-Oncology.” Nature Communications 12 (1): 5049.
Citation Format: Alisee Huglo, Shelley Hedwards, Mitchell Lawrence, Richard Rebello, Ashlee Clark, Gail Risbridger, Renea Taylor, Denis Drygin, Mustapha Haddach, Katherine M. Hannan, Ross D. Hannan, Luc Furic. PMR-116, a novel inhibitor of ribosome biogenesis with antitumor activity in preclinical models of prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr PR006.