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首页> 美国卫生研究院文献>Neuro-Oncology >DIPG-35. A NOVEL HDAC INHIBITOR IN NEW PATIENT-DERIVED DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG) MODELS
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DIPG-35. A NOVEL HDAC INHIBITOR IN NEW PATIENT-DERIVED DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG) MODELS

机译：DIPG-35。新型患者源性弥漫性内在神经胶质胶质瘤（DIPG）模型中的新型HDAC抑制剂

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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.
机译：弥漫性桥脑神经胶质瘤（DIPG）仍然是普遍致命的儿童期癌症，中位生存期不到一年。由于不可能进行手术切除并且传统的细胞毒性化学疗法的疗效非常有限，因此局部放射仍然是护理的标准。在其他尸检衍生的DIPG细胞培养成功的基础上，我们创建了一种新型的患者衍生的细胞培养物PBT-14FHTC，其特征在于H3FA3，TP53的突变以及PDGFRα和cKIT的扩增。先前的研究证明了泛HDAC抑制剂panobinostat在体内和体外抵抗DIPG的功效，尽管会产生耐药性。由于这种抗药性，以及panobinostat血脑屏障的渗透性有限，因此确定能够靶向DIPG的其他表观遗传药物至关重要。下一代HDAC抑制剂的筛选确定了Quisinostat，这是一种对HDAC1具有更高选择性的HDAC抑制剂。体外研究表明，针对特征明确的患者衍生DIPG细胞培养物SU-DIPG-XIII和SU-DIPG-XVII的IC50 <50 nM，以及在其他患者衍生培养物（如SU-DIPG-S）中相似的低nM功效IV，VUMC-DIPG-10和我们的新PBT-14FHTC。对于体内测试，我们开发了一种原位异种移植模型，该模型使用了患者源DIPG细胞，该细胞被CMV-mCherry-荧光素酶转化，可以通过生物发光IVIS成像进行评估，而不会伤害或安乐死该对象。使用我们的患者源性原位异种移植物DIPG小鼠模型，目前正在对喹诺司他作为单一药物，与其他表观遗传调节剂联合以及与放射结合的体内功效进行研究。

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