DIPG-05. COMBINATION OF SYNTHETIC RETINOID FENRETINIDE WITH RECEPTOR TYROSINE KINASE INHIBITOR PONATINIB AS A POTENTIAL NEW APPROACH AGAINST DIFFUSE INTRINSIC PONTINE GLIOMA
| Autor: | Nicole Yeung, Jie Liu, Santosh Valvi, Maria Tsoli, Han Shen, Laura Franshaw, Swapna Joshi, David S. Ziegler |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Cancer Research Receptor Protein-Tyrosine Kinases Pharmacology Pazopanib Abstracts 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Glioma medicine Vorinostat Phosphoinositide 3-kinase biology Ponatinib medicine.disease 030104 developmental biology Fenretinide Oncology chemistry 030220 oncology & carcinogenesis biology.protein Cancer research Neurology (clinical) Platelet-derived growth factor receptor medicine.drug |
| Zdroj: | Neuro-Oncology. 19:iv5-iv6 |
| ISSN: | 1523-5866 1522-8517 |
| Popis: | Diffuse Intrinsic Pontine Gliomas (DIPGs) are the most devastating of all brain tumours. They mostly affect young children and, as there are no effective treatments, almost all will die of their tumour within 12 months. We performed a high throughput screen (HTS) of 3500 clinically available compounds, which identified fenretinide among the top 33 most active agents against DIPG. In an attempt to find novel combination therapies, which could enhance the cytotoxic efficacy of fenretinde we performed a combination HTS based on the remaining 32 agents together with 50 chemotherapeutic agents against fenretinide. This approach identified drugs that enhanced fenretinide activity including Ion channel inhibitors (ivermectin, halofantrine, diphenylhydantoin), neurotransmitter receptor antagonist (GR-127935), receptor tyrosine kinases (RTKs) inhibitors (ponatinib, pazopanib) and histone deacetylase (HDAC) inhibitor saha. These promising 7 combinations were selected for further investigation in vitro using cytotoxicity assays, colony formation assays, while the best combination was further validated by flow cytometry assessing apoptotic events and western blotting to elucidate mechanisms of action. When tested against a panel of four neurosphere forming DIPG cultures, only ponatinib was found to uniformly enhance the anti-proliferative effects of fenretinide. Colony formation assays showed that fenretinide combined with ponatinib, pazopanib, GR127935, and diphenylhydantoin led to significantly reduced colony formation both with and without irradiation. Flow cytometric analysis enhanced apoptotic events in the combination treated cells. Furthermore we found that although fenretinide combination inhibited the PDGFR/PI3K pathway, these effects didn’t appear to be mediated at the gene expression level. In vivo experiments examining the therapeutic efficacy of fenretinide/irradiation and ponatinib combinations are currently undergoing using an orthotopic model of DIPG. Preliminary results indicate that delivery of fenretinide with irradiation could extend the survival of mice. This novel and potentially effective DIPG treatment strategy is readily translatable to clinical trial. |
| Databáze: | OpenAIRE |
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