METTL3 IO abstract for ENA

STC-15, an oral small molecule inhibitor of the RNA methyltransferase METTL3, inhibits tumour growth through activation of anti-cancer immune responses associated with increased interferon signalling, and synergises with T cell checkpoint blockade

Authors: Yaara Ofir-Rosenfeld¹, Lina Vasiliauskaitė¹, Claire Saunders^1*, Alexandra Sapetschnig¹, Georgia Tsagkogeorga^1,2, Mark Albertella¹⁺, Marie Carkill³, Jezrom Self-Fordham³, Josefin-Beate Holz¹ and Oliver Rausch¹

¹Storm Therapeutics Ltd, Cambridge, UK

²Milner Therapeutics Institute, University of Cambridge, Cambridge, UK

³Charles River, Portishead, UK

^*Current address: UCL Cancer Institute, London, UK

⁺Current address: Oncology R&D, AstraZeneca, Cambridge UK

Keywords (3): Novel agent, METTL3, Immuno-oncology

Conflict of interest:

MA is a stockholder of Storm Therapeutics.

YOR, LV, CS, AS, GT, MA, JBH and OR are current/former employees/consultants of Storm Therapeutics.

MC and JSF are employees of Charles River.

Background

METTL3 is an RNA methyltransferase responsible for the deposition of N-6-methyladenosine (m⁶A) modification on mRNA and long non-coding RNA (lncRNA) targets, to regulate their stability, splicing, transport and translation. Small molecule inhibitors of METTL3 catalytic activity have previously demonstrated direct anti-tumour efficacy in models of acute myeloid leukemia (AML). Here we present pre-clinical data showing that the orally bioavailable small molecule METTL3 inhibitor STC-15 inhibits cancer growth and induces anti-cancer immunity.

Materials & Methods

To characterise transcriptomic changes following METTL3 inhibition, RNA sequencing studies were performed across a panel of cancer cell lines treated with STC-15. Induction of specific genes was validated by qPCR and Western Blots. The functional consequence of the upregulation of innate immune pathways was investigated in vitro using a co-culture system of SKOV3 ovarian cancer cells and human peripheral blood mononuclear cells (PBMC), and animal studies using subcutaneous A20 and MC38 syngeneic tumour models.

Results

Inhibition of METTL3 by STC-15 in cancer cell lines leads to prominent upregulation of genes associated with innate immunity, such as those in the interferon (IFN) signalling pathway. Transcription of type-I and type-III IFNs was activated following STC-15 treatment, in agreement with the expression of many Interferon Stimulated Genes (ISG). Cells treated with STC-15 accumulated double-stranded RNA (dsRNA), suggesting that activation of IFN signalling is triggered by innate pattern recognition sensors.

In an in vitro co-culture system, STC-15 demonstrated strong and dose-dependent enhancement of PBMC-mediated killing of cancer cells that occurred at concentrations where STC-15 caused little or no direct killing of cancer cells in the absence of PBMCs.

In MC38 colorectal and A20 lymphoma syngeneic models, oral treatment of immune-competent tumour bearing mice with STC-15 significantly inhibited tumour growth. Combination of STC-15 with anti-PD1 antibody resulted in significant tumour regression in both models, with mice remaining tumour-free until the end of study, long after treatment ceased. Even when regressed mice from the A20 model were re-challenged with a new batch of A20 cells, no new tumour growth was observed, further demonstrating the induction of durable anti-tumour immunity.

Conclusions

In pre-clinical cancer models, STC-15 treatment results in activation of innate immune pathways, inhibits tumour growth and enhances the anti-tumour properties of anti-PD1 therapy to generate a durable anti-tumour immune response. These data provide the rationale for the development of STC-15 both as monotherapy and in combination with checkpoint inhibition for the treatment of solid tumour malignancies. A Phase I, First-in-Human clinical trial is planned to begin in 2022.

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