| Title: |
DIPG-29. A CONNECT CONSORTIUM PRECLINICAL STUDY IDENTIFIES MEK INHIBITION AND RADIATION AS POTENTIAL COMBINATION PARTNERS FOR THE ALK2 INHIBITOR TP-0184 IN ACVR1-MUTANT DMG |
| Authors: |
Rogers, Rebecca; Tsoli, Maria; Kumar, Shiva Senthil; Potente, Elisabet Fernandez; Biery, Matt; Grabovska, Yura; Mackay, Alan; Carvalho, Diana; Pereria, Rita; Burford, Anna; Sejdiu, Drenusha; Ruddle, Ruth; Gabel, Florian; Raynaud, Florence; Yadavilli, Sridevi; Mizoguchi, Sean; Subramaniam, Bavani; Kilburn, Lindsey; Hwang, Eugene; Nazarian, Javad; Vitanza, Nicholas; Ziegler, David; Drissi, Rachid; Jones, Chris |
| Source: |
Neuro-Oncology ; volume 25, issue Supplement_1, page i19-i19 ; ISSN 1522-8517 1523-5866 |
| Publisher Information: |
Oxford University Press (OUP) |
| Publication Year: |
2023 |
| Description: |
Somatic mutations in ACVR1, which encodes the serine/threonine kinase ALK2, are found in 20-25% of DMG-H3K27 patients. Treatment of ACVR1-mutant orthotopic xenografts with multiple chemotypes of ALK2 inhibitors (ALK2i) results in extended survival in vivo but, as single agents, these inhibitors are unable to achieve a complete anti-tumour response. To identify novel combination strategies alongside ALK2 inhibition, five international laboratories pooled resources to evaluate the ALK2i TP-0184 across 26 patient-derived DMG-H3K27 models in vitro, demonstrating GI50 values of ~0.5-10uM, although with no significant difference between ACVR1-mutant and wild-type. Genome-scale CRISPR screens of ALK2i-treated ACVR1-mutant models revealed specific genetic dependencies in critical nodes of several signalling pathways including MTOR, as well as PPP2R1A, known to play a role in MAPK pathway activation. Biomarker analysis showed inhibition of phospho-SMAD1/5/9 by western blot, with RNAseq and proteomic analysis indicating downstream signalling consequences in BMP/SMAD signalling following TP-0184 treatment. We observed synergistic pharmacological interactions between TP-0184 and both everolimus (mTORi) and trametinib (MEKi) in 7 to 8 ACVR1-mutant DMG models, respectively, with the latter validated across laboratories using orthogonal assays. Importantly, combining TP-0184 with radiation in vitro showed a profound radiosensitisation effect of the ALK2i in three ACVR1-mutant models using both clonogenic and cell viability assays in multiple laboratories, in part due to an observed activation of phospho-SMAD1/5/9 by radiation. Finally, in vivo tolerability and pharmacokinetic assays in multiple immuno-compromised and immune-competent mouse strains suggested a dose of 150mg/kg TP-0184 and 0.4mg/kg trametinib for use in in vivo efficacy studies, with good CNS penetrance of both drugs in excess of in vitro GI50 values. Such studies have been initiated in six DMG-H3K27 models across our laboratories to robustly assess the ... |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| DOI: |
10.1093/neuonc/noad073.076 |
| Availability: |
https://doi.org/10.1093/neuonc/noad073.076; https://academic.oup.com/neuro-oncology/article-pdf/25/Supplement_1/i19/50575164/noad073.076.pdf |
| Rights: |
https://creativecommons.org/licenses/by-nc/4.0/ |
| Accession Number: |
edsbas.E205F6F1 |
| Database: |
BASE |