DIPG-22. A NOVEL ROLE FOR ACVR1/ALK2 IN REGULATING CHOLESTEROL BIOSYNTHESIS PROVIDES A NEW COMBINATORIAL THERAPEUTIC APPROACH FOR PATIENTS WITH DMG

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Abstract BACKGROUND The discovery of somatic mutations in ACVR1, which encodes the serine/threonine kinase ALK2, in 20-25% of diffuse midline glioma H3K27-altered (DMG-H3K27) patients has led to the development of numerous chemotypes of ALK2 inhibitor (ALK2i). However, in models of ACVR1-mutant DMG-H3K27 the efficacy of single-agent ALK2i’s has been modest and new combinatorial treatment approaches are desperately needed. METHODS We performed unbiased combinatorial genetic and drug screens in patient-derived ACVR1-mutant DMG-H3K27 cells in vitro, using multiple chemotypes of ALK2i. We also generated in vitro transcriptomic, proteomic and metabolomic profiles of three ACVR1-mutant DMG-H3K27 models following ALK2i treatment. RESULTS The top ALK2i sensitising CRISPR hits (vehicle vs. ALK2i) were analysed using gene set enrichment analysis (GSEA) which revealed specific genetic dependencies in cholesterol synthesis/regulation following both M4K2009 and TP-0184 treatment. The top CRISPR hits included multiple key nodes of cholesterol biosynthesis such as HMGCR (HMG-CoA>mevalonate), LSS (squalene-2-2-epoxide>lanosterol) and DHCR24 (lanosterol>cholesterol). These hits were pharmacologically mirrored in the top hits identified from the drug screen, including drugs that either directly or indirectly target cholesterol synthesis. Integration of the multi-omic data revealed a raft of changes associated with cholesterol biosynthesis/efflux. The expression of HMGCR/HMGCS1 (cholesterol synthesis) and LXR/ABCA1 (cholesterol export) were down and upregulated, respectively, with metabolomic data showing a reduction in cholesterol and it’s derivative 4-cholesten-3-one and an increase in desmosterol, an immediate precursor to cholesterol synthesis. Highly synergistic interactions were observed between multiple ALK2i and a panel of pharmacological agents targeting the cholesterol synthesis/efflux pathway, including routinely used drugs such as simvastatin and lovastatin, clinically well-tolerated and with good CNS penetrance in immuno-compromised and immune-competent mouse models, in whom in vivo combination studies are ongoing. CONCLUSIONS These data provide evidence for a previously unappreciated link between ALK2 signalling and metabolism, and identify readily translatable combination partners for ALK2i in the clinic.

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