# Preclinical drug screen identifies WEE1 inhibitor and vinca alkaloid as a combination treatment concept for Li-Fraumeni syndrome medulloblastoma

## TL;DR

A drug screen found that combining a WEE1 inhibitor with vincristine could be a safe and effective treatment for medulloblastoma in Li-Fraumeni syndrome patients.

## Contribution

Identified a novel combination therapy using a WEE1 inhibitor and vincristine for TP53-mutant medulloblastoma in Li-Fraumeni syndrome.

## Key findings

- The combination of adavosertib and vincristine showed high activity against TP53-mutant medulloblastoma cells.
- WEE1 inhibition reduced tumor growth in both in vitro and in vivo models of TP53-mutant medulloblastoma.
- The drug combination exhibited low genotoxicity in LFS fibroblasts and mouse models.

## Abstract

Li-Fraumeni syndrome (LFS) is characterized by constitutional pathogenic TP53 mutation and increased risk of cancer development, including Sonic Hedgehog-activated medulloblastoma (SHH-MB). In LFS patients, radiation and DNA-damaging agents can exhibit lower efficiency and cause secondary malignancies. To identify efficacious, safe chemotherapeutic approaches for LFS-associated SHH-MB, 333 compounds were screened in in vitro TP53mut brain tumor cell lines. The combination of WEE1 inhibitor adavosertib and vinca alkaloid vincristine demonstrated the highest activity, which was validated in TP53mut SHH-MB patient-derived organoids. Low genotoxicity of these compounds was determined in vitro in LFS fibroblasts, and in vivo in the LFS mouse model. Despite the drugs’ limited efficacy in the in vivo PDX model, WEE1 knockdown led to significant growth reduction in in vitro and in vivo TP53mut SHH-MB models. Our findings identify WEE1 as a promising target in LFS SHH-MB, suggesting its inhibition combined with vincristine treatment as a potential chemotherapeutic strategy.

•Drug screen identified adavosertib and vincristine as top hits against LFS SHH-MB•Patient expression signatures supported TP53mut SHH-MB sensitivity to adavosertib•Adavosertib and vincristine combination showed low toxicity in LFS mouse model•Knockdown of adavosertib target WEE1 reduced growth of TP53mut SHH-MB models

Drug screen identified adavosertib and vincristine as top hits against LFS SHH-MB

Patient expression signatures supported TP53mut SHH-MB sensitivity to adavosertib

Adavosertib and vincristine combination showed low toxicity in LFS mouse model

Knockdown of adavosertib target WEE1 reduced growth of TP53mut SHH-MB models

Biological sciences; Cancer systems biology; Natural sciences; Pharmacology; Systems biology