Author: Ferreira, Rita ; Rebello, Richard ; Furic, Luc ; Drygin, Denis ; Hannan, Ross ; Panov, Konstantin ; Haddach, Mustapha ; Hein, Nadine ; Huglo, Alisee ; Kusnadi, Eric

AbstractIntroduction: Inhibition of RNA Polymerase I, the enzyme responsible for the synthesis of ribosomal RNAs, the nucleic scaffold of ribosomes, has been proven as a novel therapeutic target as most cancer cells are "addicted" to ribosome biogenesis.Methods: In collaboration with Pimera Inc, we developed and tested the efficacy of a second generation RNA polymerase I inhibitor, PMR-116, in various pre-clinical cancer models. On-target activity of PMR-116 was confirmed in peripheral blood cells isolated from patients with solid tumors enrolled in a phase I trial of PMR-116.Results: PMR-116 potently inhibits Pol I transcription with ~200 fold higher selectivity towards Pol I compared to Pol II transcription. PMR-116 inhibits rRNA synthesis by stalling the Pol I complex at the rDNA promoter preventing promoter escape and consequently elongation. PMR-116 anti-cancer activity was evaluated against a panel of over 100 cancer cell lines representative of 20 major types of solid and haematological malignancies. This new Pol I inhibitor exhibited broad anti-proliferative and cytotoxic activity with an IC50 ranging from 32-4500nM and a median IC50 of 300nM. In contrast, cells derived from normal tissues were significantly less sensitive (IC50 ranging from 6-33μM).In vivo, PMR-116 significantly improved survival and reduce tumor burden in several preclinical models such as Vk*MYC transgenic model of indolent multiple myeloma, CT26 xenograft model of colorectal cancer, MMTV-PyMT transgenic model of metastatic breast cancer, mixed-lineage leukemia (MLL)-eleven nineteen leukemia (ENL)+Nras acute myeloid leukemia (+/-p53 mutation) and patient-derived xenografts of prostate cancer and AML.In a phase I trial of PMR-116, on-target activity of PMR-116 was observed in cells derived from the peripheral blood.Conclusion: PMR-116 significantly reduced cancer growth in a wide range of tumor models, including GEMM, syngeneic and PDX models. PMR-116 is undergoing clinical testing in phase I in solid tumors with the objective to determine maximum tolerated dose and identify a phase II dose.Citation Format: Luc Furic, Nadine Hein, Rita Ferreira, Konstantin Panov, Alisee Huglo, Richard Rebello, Eric Kusnadi, Denis Drygin, Mustapha Haddach, Ross Hannan. PMR-116, a second generation RNA Polymerase I inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3326.

02 Jun 2023·Cancer Research

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

Author: Haddach, Mustapha ; Rebello, Richard ; Hannan, Katherine M. ; Huglo, Alisee ; Clark, Ashlee ; Hannan, Ross D. ; Hedwards, Shelley ; Taylor, Renea ; Risbridger, Gail ; Drygin, Denis ; Furic, Luc ; Lawrence, Mitchell

AbstractAdvanced 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.

15 Jun 2022·Cancer Research

Abstract 2155: PMR-116, a novel inhibitor of ribosome biogenesis with antitumor activity in preclinical models of prostate cancer

Author: Hannan, Katherine ; Furic, Luc ; Rebello, Richard ; Haddach, Mustapha ; Huglo, Alisee ; Risbridger, Gail ; Lawrence, Mitchell ; Hannan, Ross ; Drygin, Denis

AbstractAdvanced 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 (Rebello et al., Clinical Cancer Research, 2016; Lawrence et al., European Urology, 2018).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 (Lawrence et al, European Urology, 2018). 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 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).Citation Format: Alisee Huglo, Richard Rebello, Mitchell Lawrence, Gail Risbridger, Denis Drygin, Mustapha Haddach, Katherine Hannan, Ross 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 American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2155.

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