Journal Article

Systems pharmacogenomics identifies novel targets and clinically actionable therapeutics for medulloblastoma

Kuchibhotla, Mani, Wainwright, Brandon J., Bhuva, Dharmesh D., Kojic, Marija, Singleton, Matthew, Andradas, Clara, Girard, Emily, Bernard, Anne, Tolson, Elissa, Endersby, Raelene, Davis, Melissa J., Olson, James M., Millar, Amanda, Taylor, Michael D., Genovesi, Laura A., Brighi, Caterina, Hassall, Emily, Gottardo, Nicholas G., Adolphe, Christelle

2021

Overview

Background Medulloblastoma (MB) is the most common malignant paediatric brain tumour and a leading cause of cancer-related mortality and morbidity. Existing treatment protocols are aggressive in nature resulting in significant neurological, intellectual and physical disabilities for the children undergoing treatment. Thus, there is an urgent need for improved, targeted therapies that minimize these harmful side effects. Methods We identified candidate drugs for MB using a network-based systems-pharmacogenomics approach: based on results from a functional genomics screen, we identified a network of interactions implicated in human MB growth regulation. We then integrated drugs and their known mechanisms of action, along with gene expression data from a large collection of medulloblastoma patients to identify drugs with potential to treat MB. Results Our analyses identified drugs targeting CDK4, CDK6 and AURKA as strong candidates for MB; all of these genes are well validated as drug targets in other tumour types. We also identified non-WNT MB as a novel indication for drugs targeting TUBB, CAD, SNRPA, SLC1A5, PTPRS, P4HB and CHEK2. Based upon these analyses, we subsequently demonstrated that one of these drugs, the new microtubule stabilizing agent, ixabepilone, blocked tumour growth in vivo in mice bearing patient-derived xenograft tumours of the Sonic Hedgehog and Group 3 subtype, providing the first demonstration of its efficacy in MB. Conclusions Our findings confirm that this data-driven systems pharmacogenomics strategy is a powerful approach for the discovery and validation of novel therapeutic candidates relevant to MB treatment, and along with data validating ixabepilone in PDX models of the two most aggressive subtypes of medulloblastoma, we present the network analysis framework as a resource for the field.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Animals / Antimitotic agents / Antineoplastic agents / Antineoplastic Agents - pharmacology / Antineoplastic Agents - therapeutic use / Bioinformatics / Biomarkers, Tumor / Biomedical and Life Sciences / Biomedicine / Brain cancer / Brain tumors / Cancer Research / Cancer therapies / Cerebellar Neoplasms - drug therapy / Cerebellar Neoplasms - etiology / Cerebellar Neoplasms - metabolism / Chemotherapy / Clinical trials / Computational Biology - methods / Cyclin-dependent kinase 4 / Cyclin-dependent kinases / Disease Models, Animal / Drug delivery / Drug Development / Drug Evaluation, Preclinical / Drug interactions / Drug target / Gene expression / Gene Expression Profiling / Gene Expression Regulation, Neoplastic - drug effects / Gene Regulatory Networks / Genetic screen / Genetic screening / Genomics / Health aspects / Homeopathy / Human Genetics / Humans / Kinases / Materia medica and therapeutics / Medicine/Public Health / Medulloblastoma / Medulloblastoma - drug therapy / Medulloblastoma - etiology / Medulloblastoma - metabolism / Metabolomics / Mice / Mice, Transgenic / Microtubule stabilization / Morbidity / Mortality / Mutagenesis / Patients / Pharmacogenetics / Pharmacogenetics - methods / Pharmacogenomics / Protein Interaction Mapping / Protein Interaction Maps / Protein interaction network / Proteins / Systems Biology / Systems Biology - methods / Therapeutic targets / Therapeutics / Transcriptome / Wnt protein / Xenograft Model Antitumor Assays / Xenografts