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Imipridones as a novel therapy for pediatric neuroblastoma

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Abstract:
Neuroblastoma is a childhood neuroendocrine tumor that accounts for 15% of all pediatric cancer-related deaths, with an under 50% survival rate for high-risk patients. Neuroblastoma tumors with the MYCN amplification display more aggressive features at diagnosis and progress more quickly during treatment. Patients with MYCN-amplified tumors have lower chances of survival after relapse/progression and are therefore especially difficult to treat. Treatments remain limited for advanced disease, calling for the development of novel therapies. Our research investigates the anti-tumor effect of a promising new class of small molecules, imipridones ONC201, ONC206, and ONC212, in neuroblastoma. Imipridones are potent anticancer drugs that have previously demonstrated effectiveness as both single agents and in synergy with other therapies for a variety of solid tumors. Imipridones induce tumor cell apoptosis by targeting mitochondrial protease ClpP. Binding to ClpP activates mitochondrial proteolysis, leading to cancer cell death. Using standard cell culture techniques, we chose the MYCN-amplified neuroblastoma cell line SK-N-BE(2) for experiments. We performed cell viability assays using CellTiter-Glo to determine dose response curves and IC50s. Imipridones ONC201, ONC206, and ONC212 all demonstrated single-agent killing in the SK-N-BE(2) cells. We also extracted cell lysates for further protein quantification studies. Western blotting confirmed markers of apoptosis and cell death, and protein studies provided insight into the mechanisms of action of imipridones on neuroblastoma cells. Further investigation is needed to determine synergy and mechanisms of synergy when imipridones are used in novel combinations with histone deacetylase (HDAC) inhibitors such as Vorinostat and Panobinostat. HDACs play a role in controlling MYCN function, and both HDAC activity and MYCN are upregulated in chemotherapy-resistant neuroblastoma. HDAC inhibitors promote cell cycle arrest and apoptosis, and have been shown to restore cell susceptibility to cytotoxic chemotherapeutic agents. Cell viability assays with Vorinostat and Panobinostat demonstrated single-agent efficacy and synergistic effects in combination with imipridones on the SK-N-BE(2) cell line. Our data reveals promise in imipridone therapy, and future studies are proposed to explore the mechanism of action of cell killing in synergistic combinations with imipridone therapy.

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Citation

Lin, Claire, "Imipridones as a novel therapy for pediatric neuroblastoma" (2021). Summer Research Symposium. Brown Digital Repository. Brown University Library. https://doi.org/10.26300/6kc5-ep63

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  • Summer Research Symposium

    Each year, Brown University showcases the research of its undergraduates at the Summer Research Symposium. More than half of the student-researchers are UTRA recipients, while others receive funding from a variety of Brown-administered and national programs and fellowships and go …
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