In:
Neuro-Oncology, Oxford University Press (OUP), Vol. 24, No. Supplement_1 ( 2022-06-03), p. i168-i169
Abstract:
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.
Type of Medium:
Online Resource
ISSN:
1522-8517
,
1523-5866
DOI:
10.1093/neuonc/noac079.627
Language:
English
Publisher:
Oxford University Press (OUP)
Publication Date:
2022
detail.hit.zdb_id:
2094060-9
