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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2022
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.
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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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