Diffuse Intrinsic Pontine Glioma (DIPG)

Within the K27M altered tumors, one of my main interest lies on a specific tumor type called Diffuse Intrinsic Pontine Glioma (DIPG). DIPG is a rare, aggressive, and malignant brain tumor which develops in a part of the brainstem called the pons and more than 80% of DIPG patients are known to harbor H3 K27M-alterations. Due to its locational characteristic, DIPG is non-surgically resectable which hugely limits its treatment options. Most children with DIPG do not live longer than 2 years after diagnosis.

Recurrent Somatic Activin A Receptor Type 1 (ACVR1) Mutation: ACVR1 mutation is present in 24% of DIPG patients.
The right schematic shows different recurrent mutations in ACVR1 overlaid with functional protein domain and exon boundaries. ACVR1 encodes ALK2 protein, or activin receptor-like kinase 2, which is a member of the Type 1 Bone Morphogenic Protein (BMP) receptor family.
Mackay et al., 2017, Cancer Cell; Zadeh and Aldape, 2014, Nature Genetics

In 2014, around 10 years ago, our Glioma Team at The Institute of Cancer Research discovered a recurrent activating mutation in the ACVR1 gene in 24% of DIPG patients. Whilst these somatic ACVR1 mutations are not yet found in other cancer types, similar germline variants have been reported in the rare congenital malformation syndrome fibrodysplasia ossificans progressiva (FOP).

When ACVR1 is mutated either in the GS domain or the intracellular kinase domain, this results in pathway activation of downstream SMAD phosphorylation and translocation into the nucleus even in the absence of a ligand. This results in active signalling and upregulation of BMP downstream effectors, such as members of the ID protein family, which then promotes cell cycle progression via activating RB and inhibiting p21. ID genes can also be activated independent of the BMP pathway via pLys27Met substitution in histone H3.3 or amplification of ID2 gene.

*In the brain, activin-ACVR1 signaling is involved in the process of myelination. The association with putative oligendendroglial precursor origins of DIPG is important to note since oligodendrocytes are defined by their singular function where they produce the myelin sheaths.

Therefore, since I joined The Glioma Team in June 2024, I have been working on targeting this ACVR1 mutation to discover novel therapeutics for rare diseases, especially DIPG. Dorsomorphin is the very first small molecule inhibitor of ALK2 , which was originally discovered during in vivo chemical library screening looking for compounds with the ability to dorsalize developing zebrafish embryos (Yu et la., 2008, Nature Chemical Biology).

A paper “Recent Advances in ALK2 Inhibitors (Rooney and Jones, 2021, ACS Publications)” expands further on how initial ALK2 inhibitors were further modified for improved potency and metabolically stable state. This blog post will have my notes on this paper.