Hall Matthew D, Odia Yazmin, Allen Joshua E, Tarapore Rohinton, Khatib Ziad, Niazi Toba N, Daghistani Doured, Schalop Lee, Chi Andrew S, Oster Wolfgang, Mehta Minesh P
Departments of1Radiation Oncology.
2Radiation Oncology.
J Neurosurg Pediatr. 2019 Apr 5;23(6):719-725. doi: 10.3171/2019.2.PEDS18480. Print 2019 Jun 1.
Diffuse intrinsic pontine gliomas (DIPGs) frequently harbor the histone H3 K27M mutation. Gliomas with this mutation commonly overexpress dopamine receptor (DR) D2 and suppress DRD5, leading to enhanced sensitivity to DRD2 antagonism. This study reports the first clinical experience with the DRD2/3 antagonist ONC201 as a potential targeted therapy for H3 K27M-mutant DIPG. One pediatric patient (a 10-year-old girl) with H3 K27M-mutant DIPG was enrolled in an investigator-initiated, IRB-approved compassionate-use study and began single-agent ONC201 treatment 1 month after completing radiotherapy. The study endpoints were clinical and radiographic response (primary) and toxicities (secondary).The patient presented with House-Brackmann grade IV facial palsy and unilateral hearing loss. MRI demonstrated a 2.3 × 2.1 × 2.8-cm pontomedullary tumor. Stereotactic biopsy confirmed H3 K27M-mutated DIPG. The tumor was treated with radiotherapy, but 1 month after completion of that treatment, the tumor and neurological symptoms showed only minimal change, and ONC201 treatment was initiated as described above. The tumor volume sequentially decreased by 26%, 40%, and 44% over the next 6 months, and remained stable at 18 months. Ipsilateral hearing normalized and the facial palsy improved to House-Brackmann grade I by 4 months. After 1 year of ONC201 treatment, 2 new lesions were identified outside of the prior high-dose radiotherapy volume. The patient was treated with dexamethasone, bevacizumab, and additional focal radiotherapy to these new tumors. These tumors remained stable in size over the subsequent 6 months on MRI. To date, no adverse events have been observed or reported due to ONC201. The patient remains clinically improved as of the latest follow-up visit, 19 months after starting ONC201 and 22 months from diagnosis. This case supports further investigation of this novel agent targeting H3 K27M-mutated DIPG.
弥漫性脑桥内在型胶质瘤（DIPG）常携带组蛋白H3 K27M突变。携带这种突变的胶质瘤通常会过度表达多巴胺受体（DR）D2并抑制DRD5，从而导致对DRD2拮抗作用的敏感性增强。本研究报告了DRD2/3拮抗剂ONC201作为H3 K27M突变型DIPG潜在靶向治疗的首例临床经验。一名患有H3 K27M突变型DIPG的儿科患者（一名10岁女孩）参加了一项由研究者发起、经机构审查委员会（IRB）批准的同情用药研究，并在完成放疗1个月后开始接受单药ONC201治疗。研究终点为临床和影像学反应（主要终点）以及毒性（次要终点）。该患者表现为House - Brackmann IV级面神经麻痹和单侧听力丧失。磁共振成像（MRI）显示一个2.3×2.1×2.8厘米的脑桥延髓肿瘤。立体定向活检证实为H3 K27M突变型DIPG。该肿瘤接受了放疗，但在放疗结束1个月后，肿瘤和神经症状仅显示出微小变化，于是按照上述方法开始了ONC201治疗。在接下来的6个月里，肿瘤体积依次缩小了26%、40%和44%，并在18个月时保持稳定。同侧听力恢复正常，面神经麻痹在4个月时改善至House - Brackmann I级。在接受ONC201治疗1年后，在先前高剂量放疗范围之外发现了2个新病灶。该患者接受了地塞米松、贝伐单抗治疗，并对这些新肿瘤进行了额外的局部放疗。在随后的6个月里，这些肿瘤在MRI上的大小保持稳定。迄今为止，未观察到或报告因ONC201引起的不良事件。截至最新一次随访，即开始使用ONC201后的19个月和诊断后的22个月，该患者的临床状况仍有改善。该病例支持对这种针对H3 K27M突变型DIPG的新型药物进行进一步研究。
