ACVR1 R206H

In cell-based studies, ALK2 inhibitors effectively attenuated activin A and BMP-induced Phosphorylated SMAD1/5 activation in fibroblasts from individuals with FOP in a dose-dependent manner. Thus, CDD-2789 is a valuable tool compound for further investigation of the biological functions of ALK2 and ALK1 and the therapeutic potential of specific inhibition of ALK2.

P2, N=113, Active, not recruiting, Clementia Pharmaceuticals Inc. | Recruiting --> Active, not recruiting | Trial completion date: Aug 2029 --> Mar 2029

cBioPortal, CanSAR Black, and existing literature affirmed the association of these destabilizing mutations with posterior fossa ependymoma, uterine corpus carcinoma, and pediatric brain cancer. The current findings suggest these deleterious nonsynonymous single nucleotide polymorphisms as potential candidates for future functional annotations and validations associated with rare conditions, further aiding the development of precision medicine in rare diseases.

P2, N=20, Recruiting, Amsterdam UMC, location VUmc | Trial completion date: Aug 2024 --> May 2025 | Trial primary completion date: Aug 2024 --> May 2025

We solve the crystal structure of the ALK2 extracellular domain complex with a Fab fragment of Rm0443 and show that Rm0443 induces dimerization of ALK2 extracellular domains in a back-to-back orientation on the cell membrane by binding the residues H64 and F63 on opposite faces of the ligand-binding site. Rm0443 could prevent heterotopic ossification in a mouse model of fibrodysplasia ossificans progressiva that carries the human R206H pathogenic mutant.

The primary DIPG human cell line HSJD-DIPG-007 highly represents this pediatric tumor, displaying the most prevalent DIPG mutations, H3F3A (K27M) and ACVR1 (R206H). Kinetic modeling and parametric imaging using the brain 18F-DPA-714 PET data enabled specific delineation of the DIPG tumor area, which is crucial for radiotherapy dose management.

Clinical trials in rare diseases with limited study populations pose unique challenges. An ideal solution for limiting risks in early clinical studies is drug repositioning - using existing clinical molecules for new disease indications. Using existing assets may also allow a more fluid transition into clinical practice. With positive study outcome, AZD0530 may provide a therapy for FOP that can be rapidly progressed due to the availability of existing safety data from 28 registered clinical trials with AZD0530 involving over 600 patients.

Introduction of H3.1K27M alone into male and female OPC cultures provides an opportunity to compare the early tumorigenic effects of H3.1K27M between the sexes in vitro . These results demonstrate that we have created an in vitro and in vivo H3.1K27M DIPG model system for the study of sex differences and tumorigenesis in DIPG.

The 2 most effective compounds inhibit PRMT5 (GSK591 and LLY-283) reducing viability >50% in adherent and spheroid screens. However a reduction in stemness, as seen in vitro¸ does not always reduce primary tumor burden. Therefore proteomic characterization of neural differentiation in the primary PDX samples is underway, and investigation into secondary tumor initiation would be warranted.Our data shows PRMT5 inhibitors are a promising new target for DIPG, specifically in ACVR1 mutant DIPG, and justifies further in vivo investigations into changes in tumor initiation capacity and exploration of rational combinations to improve survival outcome.