Abstract 542P
Background
Li-Fraumeni Syndrome (LFS) is a genetic disorder characterized by constitutional pathogenic TP53 mutation. The affected individuals are predisposed to develop various types of cancer, frequently brain tumors. Radiation and DNA damaging agents tend to show decreased efficacy and increased toxicity in LFS patients. This study aims to find an efficacious and safe therapeutic approach for LFS-associated brain tumors.
Methods
A custom library consisting of 345 compounds was designed to target a total of 61 proteins. In vitro drug screening was carried out in two TP53mut brain cancer cell lines (SJ-GBM2 and UW228-2) and primary fibroblasts obtained from a LFS patient. The performance of each drug was evaluated based on the efficacy (cell viability assay) and genotoxicity (micronucleus assay). Subsequently, selected compounds were tested in combinations using cancerous cell lines and in vitro patient-derived xenograft (PDX) organoid cultures.
Results
As a result of in vitro screening, we found 42 compounds that showed favorable toxicity in cancer cell lines compared to primary LFS fibroblasts. From these drugs, 26 caused little to no genotoxic effect measured by DNA damage in primary LFS fibroblasts. Inhibitors of ATM/ATR, CHK1/CHK2, and WEE1, as well as microtubule-associated compounds passed a validation step and were selected for combination testing. The combination of WEE1 inhibitor adavosertib and vinca alkaloid vincristine demonstrated the highest efficiency in cancer cell lines, which was later confirmed in in vitro PDX cultures of LFS-associated brain tumors.
Conclusions
Adavosertib and vincristine were identified as a drug combination that eradicates TP53mut cancer cells without inducing DNA damage in normal tissues. This qualifies them as a novel and promising therapeutic approach for LFS patients diagnosed with brain tumors. The further steps include confirming the efficacy and safety of adavosertib and vincristine in vivo using brain tumor PDXs and LFS mouse models.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
ADDRess consortium.
Funding
Federal Ministry of Education and Research (BMBF).
Disclosure
All authors have declared no conflicts of interest.
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