PDTM-44. ROLE OF ONC-206 IN REGULATING MEDULLOBLASTOMA TUMOR PROGRESSION
Abstract Medulloblastoma (MB) is the most common malignant brain tumor in children. Of the four different sub-groups, the Sonic Hedgehog (SHH) subgroup accounts for about 30% of human MBs. The current standard of care (resection, cranio-spinal irradiation, and chemotherapy) for MB is typically ineff...
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Veröffentlicht in: | Neuro-oncology (Charlottesville, Va.) Va.), 2019-11, Vol.21 (Supplement_6), p.vi196-vi197 |
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Sprache: | eng |
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Zusammenfassung: | Abstract
Medulloblastoma (MB) is the most common malignant brain tumor in children. Of the four different sub-groups, the Sonic Hedgehog (SHH) subgroup accounts for about 30% of human MBs. The current standard of care (resection, cranio-spinal irradiation, and chemotherapy) for MB is typically ineffective for SHH MB in non-infants and those with metastatic disease. Survivors are frequently beset with long-term side effects including cognitive deficiencies and a severely impaired quality of life. Taken together, there is a critical need for novel targeted therapies for SHH MB. Recently, promising preclinical and clinical results have been obtained in a variety of cancers treated with a small molecule antagonist, ONC-201, which acts against DRD2, a G-protein coupled receptor that is widely expressed in MBs and regulates pro-survival pathways in tumors. In the present study we report the activity of ONC-201 and another DRD2 antagonist, ONC-206, which binds DRD2 with increased affinity. We tested three different MB cell lines with varied levels of DRD2 expression against these drugs, and consistently observed increased cell death at lower doses of ONC-206 compared to ONC-201. Following literature reports about the mechanism of action of ONC-201, we also evaluated the role of ClpP gene in MB cell lines. ClpP is a mitochondrial protease that has been shown to directly bind ONC 201. We observed a decrease in the expression of this gene after treatment of MB cell lines with ONC-206. Current studies are focusing on exploring the mechanism by which ONC-206 affects MB growth and metastasis. Dissecting this mechanism will be pivotal in predicting the role of this small molecule as a pre-clinical therapeutic for MB treatment. |
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ISSN: | 1522-8517 1523-5866 |
DOI: | 10.1093/neuonc/noz175.819 |