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- W2809518629 abstract "Diffuse intrinsic pontine glioma (DIPG) remains a universally fatal childhood cancer with a median survival of less than 1 year. Focal radiation remains the standard of care as surgical resection is impossible and conventional cytotoxic chemotherapy has very limited efficacy. Building on the success of other autopsy-derived DIPG cell cultures, we have created a novel patient-derived cell culture, PBT-14FHTC, characterized by mutations in H3FA3, TP53, and amplifications in PDGFRα and cKIT. Previous work has demonstrated the efficacy of panobinostat, a pan-HDAC inhibitor, against DIPG in vitro and in vivo, though resistance develops. Due to this resistance, as well as the limited blood-brain barrier penetration of panobinostat, it is critical to identify other epigenetic agents able to target DIPG. A screen of next generation HDAC inhibitors identified quisinostat, an HDAC inhibitor with a greater selectivity of HDAC1. In vitro studies demonstrate a IC50 < 50 nM against well-characterized patient-derived DIPG cell cultures SU-DIPG-XIII and SU-DIPG-XVII, as well as similar low nM efficacy in other patient-derived cultures such as SU-DIPG-IV, VUMC-DIPG-10, and our new PBT-14FHTC. For in vivo testing, we developed an orthotopic xenograft model using patient-derived DIPG cells transformed with CMV-mCherry-luciferase that can be evaluated by bioluminescence IVIS imaging without harming or euthanizing the subject. In vivo efficacy studies of quisinostat as a single agent, in combination with other epigenetic modulating agents, and in combination with radiation are currently underway using our patient-derived orthotopic xenograft DIPG mouse model." @default.
- W2809518629 created "2018-06-29" @default.
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- W2809518629 date "2018-06-01" @default.
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- W2809518629 title "DIPG-35. A NOVEL HDAC INHIBITOR IN NEW PATIENT-DERIVED DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG) MODELS" @default.
- W2809518629 doi "https://doi.org/10.1093/neuonc/noy059.128" @default.
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