Novel combination therapy targeting rDNA transcription and Histone Deacetylation Provides Effective Treatment for Multiple Myeloma, and Synergises in Bortezomib-Resistant MM

Background: Multiple myeloma (MM) requires combination drug therapies to delay acquired drug resistance and clinical relapse. We co-developed CX-5461, a highly-selective inhibitor of RNA polymerase I-mediated rDNA transcription(1), currently in phase I trials for relapsed haematological malignancies (Peter Mac). CX-5461 produces a targeted nucleolar DNA damage response (DDR), triggering both a p53-dependent and -independent nucleolar stress response and killing malignant cells while sparing normal cells(2,3). Single-agent CX-5461 provides an impressive survival benefit in mouse models of B-cell lymphoma, acute myeloid leukaemia and now MM(2,4,5). However, drug resistance eventually occurs, confirming the need for combination therapies. Aim: To test the efficacy of CX-5461 in combination with the histone deacetylase inhibitor panobinostat, (prioritised from a boutique high-throughput screen of anti-myeloma agents), with a focus on the setting of resistance to proteasome-inhibitors (PIs). Methods: We assessed the impact of CX-5461 and panobinostat on overall survival in mouse models of MM, then surveyed the effects on cellular response and molecular markers of DDR. We developed bortezomib-resistant cell lines and an in vivo model of bortezomib-resistance to test this combination in the setting of PI-resistance. Results: CX-5461 in combination with panobinostat provides a significant survival advantage in both the transplanted Vk*MYC and the 5T33/KaLwRij models, with minimal bone marrow toxicity

Abstract IA10: Drugging the ribosome at the level of synthesis and translation to treat solid and hematologic cancers

Recent findings by our group have been instrumental in the development of the novel selective inhibitors of RNA Polymerase I (Pol I) (Drygin et al., Cancer Research, 2011; Bywater et al. Cancer Cell, 2012). This work has led to the fundamental discovery that ribosomal gene transcription by Pol I is not simply a “housekeeping” process in cancer cells but is highly regulated to maintain their viability (Bywater et al. Nature Reviews Cancer, 2013). Strikingly, inhibition of Pol I transcription shows a profound selectivity for malignant over normal cells in preclinical studies. As with the majority of targeted therapies, despite initial favorable responses to approaches that target ribosome synthesis and/or function in MYC-driven lymphoma models, resistant disease emerges. It is increasingly clear that maximizing the inhibition of key signaling networks as a whole improves anti-tumor response. The well-established reliance of MYC-driven malignancies on elevated rates of ribosome biogenesis, mTORC1/eIF4E-driven protein synthesis, and cell growth makes them vulnerable to therapeutic strategies that target the ribosome. Thus we hypothesized that the simultaneous targeting of the ribosome at multiple points would antagonize the development of acquired resistance and consequently prolong survival in MYC-driven cancer models. We will present data to demonstrate that targeting both ribosome synthesis and function through the combination of novel inhibitors of RNA polymerase I transcription, and PI3K/AKT/mTOR signaling inhibitors or PIM Kinase inhibitors provides a significant increase in survival compared to treatment with single agents (Devlin et al., Cancer Discovery 2016; Rebello et al., Clinical Cancer Res. 2016). We will also discuss the molecular mechanism by which multipoint targeting of the ribosome synergizes to increase survival. Finally we will discuss our collaboration with Pimera, Inc. to develop highly selective second generation RNA Pol I inhibitors. The lead compound PMR-116 is showing exceptional activity in transgenic models of malignancy, including MLL-ENL AML and Vk*MYC driven multiple myeloma. We anticipate this compound will enter the clinic in 2017. Citation Format: Ross D. Hannan, Nadine Hein, Katherine M. Hannan, Gretchen Poortinga, Elaine Sanij, Jirawas Sornkom, Kylee MacLachlan, Andrew Cuddihy, Carleen Cullinane, Luc Furic, Denis Drygin, Mustapha Haddach, Simon Harrison, Grant McArthur, Richard B. Pearson. Drugging the ribosome at the level of synthesis and translation to treat solid and hematologic cancers. [abstract]. In: Proceedings of the AACR Special Conference on Translational Control of Cancer: A New Frontier in Cancer Biology and Therapy; 2016 Oct 27-30; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2017;77(6 Suppl):Abstract nr IA10. ©2017 American Association for Cancer Research

First-in-Human RNA Polymerase I Transcription Inhibitor CX-5461 in Patients with Advanced Hematologic Cancers: Results of a Phase I Dose-Escalation Study

RNA polymerase I (Pol I) transcription of ribosomal RNA genes (rDNA) is tightly regulated downstream of oncogenic pathways, and its dysregulation is a common feature in cancer. We evaluated CX-5461, the first-in-class selective rDNA transcription inhibitor, in a first-in-human, phase I dose-escalation study in advanced hematologic cancers. Administration of CX-5461 intravenously once every 3 weeks to 5 cohorts determined an MTD of 170 mg/m(2), with a predictable pharmacokinetic profile. The dose-limiting toxicity was palmar-plantar erythrodysesthesia; photosensitivity was a dose-independent adverse event (AE), manageable by preventive measures. CX-5461 induced rapid on-target inhibition of rDNA transcription, with p53 activation detected in tumor cells from one patient achieving a clinical response. One patient with anaplastic large cell lymphoma attained a prolonged partial response and 5 patients with myeloma and diffuse large B-cell lymphoma achieved stable disease as best response. CX-5461 is safe at doses associated with clinical benefit and dermatologic AEs are manageable.SIGNIFICANCE: CX-5461 is a first-in-class selective inhibitor of rDNA transcription. This first-in-human study establishes the feasibility of targeting this process, demonstrating single-agent antitumor activity against advanced hematologic cancers with predictable pharmacokinetics and a safety profile allowing prolonged dosing. Consistent with preclinical data, antitumor activity was observed in TP53 wild-type and mutant malignancies