DIPG-06. PRECLINICAL EVALUATION OF A NOVEL ACVR1 INHIBITOR IN DIFFUSE INTRINSIC PONTINE GLIOMAS

Diffuse intrinsic pontine glioma (DIPG) is an incurable brain disease in children. DIPG is refractory to current available therapies. Hence, new therapeutic approaches are urgently needed. About 80% of DIPGs harbor histone 3 lysine to methionine (H3K27M) mutation, in H3-3A (encoding H3.3 histone) and H3C2 (encoding H3.1 histone) genes. One quarter of DIPG tumors harbor somatic mutations in ACVR1 gene, encoding the serine/threonine kinase receptor ALK2. ACVR1 mutations co-segregate with H3.1K27M mutation, representing a specific tumour subtype with distinct clinicopathological and molecular features. These mutations are associated with an aberrant activation of SMAD pathway believed to promote cell proliferation in DIPGs. In the present studies, we evaluated the effectiveness of an orally bioavailable ALK inhibitor, TP-0184 (Tolero Pharmaceuticals) in ACVR1 mutated (ACVR1-mut) and wildtype (ACVR1- WT) DIPG models. Our results indicate that TP-0184 effectively inhibited cell proliferation in primary-patient derived DIPG cell lines. However, we did not observe any selectivity toward ACVR1 mutations. TP-0184 does not induce cell death, but rather cell cycle inhibition, arresting cells in G(2)/M phase. Interestingly, when treated with ionizing radiation (IR), ACVR1-mut cells preferentially activated SMAD signaling compared to ACVR1-WT. We are currently evaluating the combination efficacy of TP-0184 with IR in our in vitro and in vivo DIPG models. Data on tumor growth kinetics, survival and the effect on SMAD signaling pathway will be presented and discussed.