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 Saunders1*, Alexandra Sapetschnig1, Georgia Tsagkogeorga1,2, 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.
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.
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.
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.