Work

Ddre-03. International Preclinical Drug Discovery and Biomarker Program Informing an Adoptive Combinatorial Trial for Diffuse Midline Gliomas

Year: 2020

Type: article

Abstract: INTRODUCTION DMG-ACT (DMG- multi-arm Adaptive and Combinatorial Trial) aims to implement a highly innovative clinical trial design of combinatorial arms for patients with diffuse midline gliomas (DMGs) at all disease stages that is adaptive to pre-clinical data generated in ten collaborating institutions. Novel drug and drug combination were tested, predictive biomarkers were identified and incorporated in clinical trial design. METHODS In vitro (n=15) and in vivo (n=8) models of DMGs across ten institutions were used to assess single and combination treatments with ONC201, ONC206, marizomib, panobinostat, 5-Azacytidine, Val-083, GDC0084 and TAK228. In vivo drug toxicity screenings were conducted using larval zebrafish model and murine PDX models. Predictive biomarkers for ONC201 and ONC206 were identified using meta-analysis, and extensive molecular assays including CRISPR, RNAseq, FACS, and IHC. RESULTS Inhibitory concentrations (IC50) were established and validated multiple preclinical models. ONC201 and ONC206, ONC201 and TAK228, ONC201 and GDC0084 showed synergism. In vivo survival assays showed increased survival for: ONC201 (p=0.01), ONC206 (p=0.01), ONC201+ONC206 (p=0.02), and ONC201+panobinostat (p=0.01). Marizomib showed toxicity in murine/zebrafish PDXs models. Murine pharmacokinetic analysis showed peak brain levels of ONC201 and ONC206 above pre-clinical IC50. Molecular testing and analyses of existing drug screen across 537 cancer cell lines validated mitochondrial protease ClpP and ATF4 as ONC201/6 targets. Predictive biomarkers of response to drug were identified. CONCLUSION Thorough preclinical testing in a multi-site laboratory setting is feasible and identified ONC201 in combination with ONC206, TAK228 and GDC0084 as promising therapeutics for DMGs.

Source: Neuro-Oncology

DOI: 10.1093/neuonc/noaa215.248