# Exploring Novel Applications: Repositioning Clinically Approved Therapies for Medulloblastoma Treatment

## TL;DR

This study explores repurposing approved cancer drugs for medulloblastoma, finding that Venetoclax, a BCL-2 inhibitor, shows promise in treating this aggressive pediatric brain tumor.

## Contribution

The study identifies Venetoclax as a potential repositioned therapy for medulloblastoma through in silico and experimental validation.

## Key findings

- Venetoclax demonstrated efficacy in medulloblastoma cell models alone and in combination with Etoposide.
- Certain drug targets correlated with survival outcomes, suggesting treatment relevance for specific genetic subgroups.
- Immune checkpoint inhibitors showed subgroup-specific relevance, with some being beneficial and others detrimental.

## Abstract

Medulloblastoma patients who relapse after standard therapies face a poor prognosis, underscoring the need for novel treatment strategies. To accelerate therapeutic discovery, we explored a drug repositioning approach by analyzing genes targeted by approved cancer drugs in relation to patient survival. Using the R2 Genomics Analysis and Visualization Platform and TCGA datasets, we identified genes associated with poor prognosis across medulloblastoma subgroups in both metastatic and non-metastatic contexts. Among the candidate therapies, the BCL-2 inhibitor Venetoclax, typically used for hematologic malignancies, emerged as a promising option. Experimental validation in medulloblastoma cell models confirmed the efficacy of Venetoclax alone and in combination with Etoposide, a standard chemotherapeutic agent. This in silico and experimental study supports the potential of drug repositioning to expand therapeutic options for medulloblastoma patients, particularly those with relapsed disease or in need of less aggressive treatments.

Background/Objectives: The advent of tyrosine kinase inhibitors (TKI), therapeutic antibodies and inducers of apoptosis has revolutionized cancer treatment, yet their application in pediatric tumors, particularly medulloblastoma, remains understudied. Understanding the expression of these targets in specific genetic subgroups could unveil potential repositioning opportunities for already approved drugs. Methods: We analyzed RNA-sequencing data from the R2 Genomics Analysis and Visualization Platform (N = 763 patients, multiple cohorts) and the TCGA database (six individual cohorts 828 patients) to assess the expression of 73 potential targets of TKIs and antibodies targeting immune checkpoint inhibitors (ICI) or membrane receptors and inducers of apoptosis. These treatments, FDA-approved or in phase II clinical trials for solid or hematologic cancers, and their targets were evaluated in both non-metastatic and metastatic patients when data was available. Additionally, we examined treatments tailored to mutated targets crucial for tumorigenesis or resistance to conventional therapies. Results: Overexpression of certain targets beyond predefined cutoff values in Kaplan–Meier analyses correlated with either prolonged or shortened overall survival. Targets associated with shorter survival suggested potentially relevant treatments, thereby highlighting the importance of defining specific treatments for distinct genetic subgroups. Notably, certain immune checkpoint inhibitors showed relevance for specific subgroups but detriment for others. As a positive control, our analysis confirmed the use of axitinib, an anti-angiogenic treatment, as demonstrated by our recent publication. Surprisingly, a treatment developed for hematological tumors, venetoclax, demonstrated potential efficacy in medulloblastoma. Conclusions: Medulloblastoma displays subtype-specific expressions of FDA-approved TKI, ICI and pro-apoptotic drug targets, impacting overall survival. Clinical trials investigating these approved treatments in medulloblastoma are therefore warranted.