MOMC-5. Systems pharmacogenomics identifies novel targets and clinically actionable therapeutics for medulloblastoma
| Autor: | Melissa J. Davis, Emily Girald, Brandon J. Wainwright, Amanda Millar, Christelle Adolphe, Emily Hassall, Mani Kuchibhotla, Matthew Singleton, Anne Bernard, Nicholas G. Gottardo, Laura A. Genovesi, Elissa Tolson, Caterina Brighi, Marija Kojic, Clara Andradas, Raelene Endersby, James M. Olson |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Medulloblastoma
medicine.medical_specialty business.industry Final Category: Multi-omics Cancer Cell growth regulation Brain tumor childhood medicine.disease Chek2 gene Supplement Abstracts Pharmacogenomics Existing Treatment medicine AcademicSubjects/MED00300 Tumor growth AcademicSubjects/MED00310 Intensive care medicine business |
| Zdroj: | Neuro-oncology Advances |
| ISSN: | 2632-2498 |
| Popis: | 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. Clearly, 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 Sonic Hedgehog and Group 3 patient-derived xenograft tumours, 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. |
| Databáze: | OpenAIRE |
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