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DIPG-49. International preclinical drug discovery and biomarker program informing an adoptive combinatorial trial for DMG
INTRODUCTION: DMG-ACT (DMG- multi-arm Adaptive and Combinatorial Trial) will implement an innovative clinical trial design of combinatorial arms for patients with DMG at all disease stages, that is adaptive to pre-clinical and correlate data generated in eight collaborating institutions. The goal of...
Autores principales: | , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9165348/ http://dx.doi.org/10.1093/neuonc/noac079.106 |
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author | Nazarian, Javad Dun, Matthew Kilburn, Lindsay Waszak, Sebastian Vitanza, Nicholas Franson, Andrea Prados, Mike Raabe, Eric Firestein, Ron Beck, Alexander Saratsis, Amanda Rotblat, Barak van Vuurder, Dannis Foster, Jessica Hulleman, Esther Kline, Cassie Gupta, Nalin Cain, Jason Koschmann, Carl Muller, Sabine |
author_facet | Nazarian, Javad Dun, Matthew Kilburn, Lindsay Waszak, Sebastian Vitanza, Nicholas Franson, Andrea Prados, Mike Raabe, Eric Firestein, Ron Beck, Alexander Saratsis, Amanda Rotblat, Barak van Vuurder, Dannis Foster, Jessica Hulleman, Esther Kline, Cassie Gupta, Nalin Cain, Jason Koschmann, Carl Muller, Sabine |
author_sort | Nazarian, Javad |
collection | PubMed |
description | INTRODUCTION: DMG-ACT (DMG- multi-arm Adaptive and Combinatorial Trial) will implement an innovative clinical trial design of combinatorial arms for patients with DMG at all disease stages, that is adaptive to pre-clinical and correlate data generated in eight collaborating institutions. The goal of the team is to rapidly identify and validate i) promising drugs and drug combinations for clinical use, and ii) predictive biomarkers of promising drugs. METHODS: In vitro (n=30) and in vivo (n=8) models of DMG across fourteen institutions were used to assess single and combination treatment of over 80 drugs and drug combinations. Predictive biomarkers of response for top candidate drugs were identified using extensive molecular assays including proteomics, CRISPR, RNAseq, ELISA, FACS, and IHC. RESULTS: Inhibitory concentration (IC50) of all drugs were established and validated across all participating sites. In vivo validation of single and combination drug assays confirmed drug efficacy as increased survival for: ONC201 (p=0.01), ONC206 (p=0.01), ONC201+ONC206 (p=0.02), ONC201+panobinostat (p=0.01). Marizomib was highly toxic in murine PDX and zebrafish larvae assays. Murine pharmacokinetic analysis showed peak brain levels of ONC201, and ONC206 above pre-clinical IC50 concentrations. Molecular testing and analyses of existing drug screen across 578 cancer cells validated mitochondrial stress and additional proteins, as the main targets induces by ONC201/6. CONCLUSION: Thorough preclinical testing in a multi-site laboratory setting identified promising therapeutics for DMGs, resulting in launch of two clinical trials (PNOC022, ONOC023). Validation of identified biomarkers are ongoing using clinical specimen as well as in vivo PDX models. |
format | Online Article Text |
id | pubmed-9165348 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-91653482022-06-06 DIPG-49. International preclinical drug discovery and biomarker program informing an adoptive combinatorial trial for DMG Nazarian, Javad Dun, Matthew Kilburn, Lindsay Waszak, Sebastian Vitanza, Nicholas Franson, Andrea Prados, Mike Raabe, Eric Firestein, Ron Beck, Alexander Saratsis, Amanda Rotblat, Barak van Vuurder, Dannis Foster, Jessica Hulleman, Esther Kline, Cassie Gupta, Nalin Cain, Jason Koschmann, Carl Muller, Sabine Neuro Oncol Diffuse Midline Glioma/DIPG INTRODUCTION: DMG-ACT (DMG- multi-arm Adaptive and Combinatorial Trial) will implement an innovative clinical trial design of combinatorial arms for patients with DMG at all disease stages, that is adaptive to pre-clinical and correlate data generated in eight collaborating institutions. The goal of the team is to rapidly identify and validate i) promising drugs and drug combinations for clinical use, and ii) predictive biomarkers of promising drugs. METHODS: In vitro (n=30) and in vivo (n=8) models of DMG across fourteen institutions were used to assess single and combination treatment of over 80 drugs and drug combinations. Predictive biomarkers of response for top candidate drugs were identified using extensive molecular assays including proteomics, CRISPR, RNAseq, ELISA, FACS, and IHC. RESULTS: Inhibitory concentration (IC50) of all drugs were established and validated across all participating sites. In vivo validation of single and combination drug assays confirmed drug efficacy as increased survival for: ONC201 (p=0.01), ONC206 (p=0.01), ONC201+ONC206 (p=0.02), ONC201+panobinostat (p=0.01). Marizomib was highly toxic in murine PDX and zebrafish larvae assays. Murine pharmacokinetic analysis showed peak brain levels of ONC201, and ONC206 above pre-clinical IC50 concentrations. Molecular testing and analyses of existing drug screen across 578 cancer cells validated mitochondrial stress and additional proteins, as the main targets induces by ONC201/6. CONCLUSION: Thorough preclinical testing in a multi-site laboratory setting identified promising therapeutics for DMGs, resulting in launch of two clinical trials (PNOC022, ONOC023). Validation of identified biomarkers are ongoing using clinical specimen as well as in vivo PDX models. Oxford University Press 2022-06-03 /pmc/articles/PMC9165348/ http://dx.doi.org/10.1093/neuonc/noac079.106 Text en © The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com |
spellingShingle | Diffuse Midline Glioma/DIPG Nazarian, Javad Dun, Matthew Kilburn, Lindsay Waszak, Sebastian Vitanza, Nicholas Franson, Andrea Prados, Mike Raabe, Eric Firestein, Ron Beck, Alexander Saratsis, Amanda Rotblat, Barak van Vuurder, Dannis Foster, Jessica Hulleman, Esther Kline, Cassie Gupta, Nalin Cain, Jason Koschmann, Carl Muller, Sabine DIPG-49. International preclinical drug discovery and biomarker program informing an adoptive combinatorial trial for DMG |
title | DIPG-49. International preclinical drug discovery and biomarker program informing an adoptive combinatorial trial for DMG |
title_full | DIPG-49. International preclinical drug discovery and biomarker program informing an adoptive combinatorial trial for DMG |
title_fullStr | DIPG-49. International preclinical drug discovery and biomarker program informing an adoptive combinatorial trial for DMG |
title_full_unstemmed | DIPG-49. International preclinical drug discovery and biomarker program informing an adoptive combinatorial trial for DMG |
title_short | DIPG-49. International preclinical drug discovery and biomarker program informing an adoptive combinatorial trial for DMG |
title_sort | dipg-49. international preclinical drug discovery and biomarker program informing an adoptive combinatorial trial for dmg |
topic | Diffuse Midline Glioma/DIPG |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9165348/ http://dx.doi.org/10.1093/neuonc/noac079.106 |
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