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MODL-04. Drug screening in Disorders with Abnormal DNA Damage Response/Repair (DADDR) andin vivo validation

INTRODUCTION: Disorders with Abnormal DNA Damage Response/Repair (DADDRs) are inherited conditions caused by constitutional mutations of DNA damage response and repair genes and are characterized by an increased cancer risk. Furthermore, affected individuals also show an elevated risk of secondary n...

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Autores principales: Kolodziejczak, Anna, Selt, Florian, Peterziel, Heike, Jamaladdin, Nora, Mack, Norman, Maass, Kendra, Kool, Marcel, Herold-Mende, Christel, El Damaty, Ahmed, Oehme, Ina, Jones, David T W, Witt, Olaf, Pajtler, Kristian W, Kratz, Christian, Pfister, Stefan M, Milde, Till
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9164948/
http://dx.doi.org/10.1093/neuonc/noac079.627
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author Kolodziejczak, Anna
Selt, Florian
Peterziel, Heike
Jamaladdin, Nora
Mack, Norman
Maass, Kendra
Kool, Marcel
Herold-Mende, Christel
El Damaty, Ahmed
Oehme, Ina
Jones, David T W
Witt, Olaf
Pajtler, Kristian W
Kratz, Christian
Pfister, Stefan M
Milde, Till
author_facet Kolodziejczak, Anna
Selt, Florian
Peterziel, Heike
Jamaladdin, Nora
Mack, Norman
Maass, Kendra
Kool, Marcel
Herold-Mende, Christel
El Damaty, Ahmed
Oehme, Ina
Jones, David T W
Witt, Olaf
Pajtler, Kristian W
Kratz, Christian
Pfister, Stefan M
Milde, Till
author_sort Kolodziejczak, Anna
collection PubMed
description INTRODUCTION: Disorders with Abnormal DNA Damage Response/Repair (DADDRs) are inherited conditions caused by constitutional mutations of DNA damage response and repair genes and are characterized by an increased cancer risk. Furthermore, affected individuals also show an elevated risk of secondary neoplasms as well as excessive toxicity, poor therapy response and increased mortality when treated with standard radiation and chemotherapy regimens. The main aim of this project is to screen for potential novel chemotherapeutic approaches for these cancer entities, and to employ faithful PDX models for in vivo validation. METHODS: In vitro drug screening was performed using a custom library composed of 345 compounds targeting 61 different proteins. For two specific DADDRs, Li-Fraumeni syndrome (LFS) and Constitutional Mismatch Repair Deficiency (CMMRD), two cancerous (glioblastoma and medulloblastoma) and one non-cancerous cell lines were selected to model each of these conditions. Performance of each drug was assessed based on its efficacy (sensitivity score) and genotoxicity (micronucleus assay). For DADDR PDX model establishment tumor material from DADDR patients is currently being injected orthotopically (brain tumors) or subcutaneously (non-brain tumors) into NSG mice. Following engraftment and expansion, the PDX models will be characterized molecularly and compared with original patient material. RESULTS AND OUTLOOK: In vitro screening revealed n=26 drugs that fulfilled the following criteria: a) favorable toxicity in cancerous cell lines compared to non-cancerous cell lines, b) little to no genotoxic effect in non-cancerous cell lines. These characteristics qualify them as potentially suitable candidates for novel therapeutic approaches specifically for DADDR patients. The hits included inhibitors of ATM/ATR, CHK1/CHK2, DHFR, mTOR and PI3K, as well as microtubule-associated compounds. Combination testing and further validation of these hits using disease-specific in vitro and in vivo PDX models is ongoing.
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spelling pubmed-91649482022-06-05 MODL-04. Drug screening in Disorders with Abnormal DNA Damage Response/Repair (DADDR) andin vivo validation Kolodziejczak, Anna Selt, Florian Peterziel, Heike Jamaladdin, Nora Mack, Norman Maass, Kendra Kool, Marcel Herold-Mende, Christel El Damaty, Ahmed Oehme, Ina Jones, David T W Witt, Olaf Pajtler, Kristian W Kratz, Christian Pfister, Stefan M Milde, Till Neuro Oncol Preclinical Models/Experimental Therapy/Drug Discovery INTRODUCTION: Disorders with Abnormal DNA Damage Response/Repair (DADDRs) are inherited conditions caused by constitutional mutations of DNA damage response and repair genes and are characterized by an increased cancer risk. Furthermore, affected individuals also show an elevated risk of secondary neoplasms as well as excessive toxicity, poor therapy response and increased mortality when treated with standard radiation and chemotherapy regimens. The main aim of this project is to screen for potential novel chemotherapeutic approaches for these cancer entities, and to employ faithful PDX models for in vivo validation. METHODS: In vitro drug screening was performed using a custom library composed of 345 compounds targeting 61 different proteins. For two specific DADDRs, Li-Fraumeni syndrome (LFS) and Constitutional Mismatch Repair Deficiency (CMMRD), two cancerous (glioblastoma and medulloblastoma) and one non-cancerous cell lines were selected to model each of these conditions. Performance of each drug was assessed based on its efficacy (sensitivity score) and genotoxicity (micronucleus assay). For DADDR PDX model establishment tumor material from DADDR patients is currently being injected orthotopically (brain tumors) or subcutaneously (non-brain tumors) into NSG mice. Following engraftment and expansion, the PDX models will be characterized molecularly and compared with original patient material. RESULTS AND OUTLOOK: In vitro screening revealed n=26 drugs that fulfilled the following criteria: a) favorable toxicity in cancerous cell lines compared to non-cancerous cell lines, b) little to no genotoxic effect in non-cancerous cell lines. These characteristics qualify them as potentially suitable candidates for novel therapeutic approaches specifically for DADDR patients. The hits included inhibitors of ATM/ATR, CHK1/CHK2, DHFR, mTOR and PI3K, as well as microtubule-associated compounds. Combination testing and further validation of these hits using disease-specific in vitro and in vivo PDX models is ongoing. Oxford University Press 2022-06-03 /pmc/articles/PMC9164948/ http://dx.doi.org/10.1093/neuonc/noac079.627 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 Preclinical Models/Experimental Therapy/Drug Discovery
Kolodziejczak, Anna
Selt, Florian
Peterziel, Heike
Jamaladdin, Nora
Mack, Norman
Maass, Kendra
Kool, Marcel
Herold-Mende, Christel
El Damaty, Ahmed
Oehme, Ina
Jones, David T W
Witt, Olaf
Pajtler, Kristian W
Kratz, Christian
Pfister, Stefan M
Milde, Till
MODL-04. Drug screening in Disorders with Abnormal DNA Damage Response/Repair (DADDR) andin vivo validation
title MODL-04. Drug screening in Disorders with Abnormal DNA Damage Response/Repair (DADDR) andin vivo validation
title_full MODL-04. Drug screening in Disorders with Abnormal DNA Damage Response/Repair (DADDR) andin vivo validation
title_fullStr MODL-04. Drug screening in Disorders with Abnormal DNA Damage Response/Repair (DADDR) andin vivo validation
title_full_unstemmed MODL-04. Drug screening in Disorders with Abnormal DNA Damage Response/Repair (DADDR) andin vivo validation
title_short MODL-04. Drug screening in Disorders with Abnormal DNA Damage Response/Repair (DADDR) andin vivo validation
title_sort modl-04. drug screening in disorders with abnormal dna damage response/repair (daddr) andin vivo validation
topic Preclinical Models/Experimental Therapy/Drug Discovery
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9164948/
http://dx.doi.org/10.1093/neuonc/noac079.627
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