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Published on: March 3, 2015
Development of a high-throughput screening platform to identify new therapeutic agents for Medulloblastoma Group 3
Inés Fallon1, Henar Hernando2, Olga Almacellas-Rabaiget2
1Oncoheroes Biosciences S.L., Barcelona, Spain; Grup d'Enginyeria de Materials, Institut Químic de Sarrià, Universitat Ramon Llull, Barcelona, 08017, Spain.
Insights
A new high throughput screening platform identifies novel therapies for Group 3 medulloblastoma (MB G3), a rare pediatric brain tumor. The platform found active compounds and synergistic drug pairs, offering hope for improved treatments.
Area of Science:
- Oncology
- Pediatric Oncology
- Drug Discovery
Background:
- Pediatric brain tumors (PBTs) are the most common childhood solid tumors.
- Medulloblastoma (MB) is the most frequent malignant PBT, with Group 3 (MB G3) having the poorest prognosis, especially with MYC amplification.
- Currently, no targeted treatments exist for MB G3.
Purpose of the Study:
- To develop and validate a high throughput screening (HTS) platform for identifying new therapeutic agents for MB G3.
- To incorporate 2D and 3D efficacy and toxicity models accounting for tumor heterogeneity and drug limitations.
- To discover novel drug candidates and combinations to overcome resistance and toxicity in MB G3.
Main Methods:
- Designed and implemented a unique HTS platform for MB G3 drug discovery.
- Utilized validated 2D and 3D cell models to assess drug efficacy and toxicity.
- Conducted a pilot HTS campaign using a 1280-compound library.
Main Results:
- Identified 8 active compounds targeting known MB pathways.
- Several identified compounds are approved or in clinical trials for PBTs.
- Discovered 3 synergistic drug pairs to combat tumor resistance, with one pair in clinical study for recurrent MB and PBTs.
Conclusions:
- The HTS platform is effective for identifying potential MB G3 therapies.
- The platform successfully identified promising drug candidates and synergistic combinations.
- These findings offer new avenues for treating high-risk pediatric brain tumors like MB G3.
Abstract:
Pediatric brain tumors (PBTs) represent about 25 % of all pediatric cancers and are the most common solid tumors in children and adolescents. Medulloblastoma (MB) is the most frequently occurring malignant PBT, accounting for almost 10 % of all pediatric cancer deaths. MB Group 3 (MB G3) accounts for 25-30 % of all MB cases and has the worst outcome, particularly when associated with MYC amplification. However, no targeted treatments for this group have been developed so far. Here we describe a unique high throughput screening (HTS) platform specifically designed to identify new therapies for MB G3. The platform incorporates optimized and validated 2D and 3D efficacy and toxicity models, that account for tumor heterogenicity, limited efficacy and unacceptable toxicity from the very early stage of drug discovery. The platform has been validated by conducting a pilot HTS campaign with a 1280 lead-like compound library. Results showed 8 active compounds, targeting MB reported targets and several are currently approved or in clinical trials for pediatric patients with PBTs, including MB. Moreover, hits were combined to avoid tumor resistance, identifying 3 synergistic pairs, one of which is currently under clinical study for recurrent MB and other PBTs.
