Targeted Therapy in Ex Vivo Medulloblastoma

项目概要/摘要 我领导了儿童肿瘤组的III期临床试验ACNS 0332，该试验评估了以下疾病的治疗方案： 患有高危髓母细胞瘤（最常见的儿科脑肿瘤）和幕上原始神经胶质瘤的儿童 神经外胚层肿瘤（sPNK 4）。该研究于2007年开始，并于2014年进行了重大修订， 当新出现的数据显示髓母细胞瘤和sPN之间的生物学差异， sPNET患者的异质性。我们停止了sPNET患者的招募，并资助了基因组分析 在该补助金的前一个周期，显示71%的非松果体sPNET患者实际上是高级别的 神经胶质瘤、室管膜瘤或非典型畸胎样横纹肌样肿瘤，尽管组织病理学显示sPNET。这 揭示了传统组织病理学的局限性，并表明当代基因组分析可以 使许多儿童免于接受没有必要和没有帮助的颅脊髓放射治疗。 在本次更新申请的目标1中，我们将基因组研究扩展到了300例髓母细胞瘤患者， study.我们收集了超过95%的患者的研究组织，并预计这些研究将揭示 1)尽管对ACNS 0332进行了强化治疗，但仍可能死于疾病的患者组，2）患者 由于临床或组织病理学观察结果（可能包括 良好预后患者的混合物（例如，那些在辐射量远低于 ACNS 0332）以及基因组学预测的预后不良的患者，这些患者应在以下方面进行不同分层： 未来 在目标2中，我们讨论了预后最差的患者的放射抵抗表型，特别是那些 扩增的MYC或MYCN。我们将从患者来源的原位组织中收集放射治疗前和放射治疗后的标本。 异种移植物（PDOX）模型（14 MYC/MYCN扩增），我们在前一个周期中生成并表征了这些模型。 这项资助;我们从四个合作者那里收到的其他PDOX模型;以及我们 生成并表征。我们将使用这些细胞系来筛选FDA批准的药物， 克服辐射抗性，并进行功能基因组筛选，以确定当 抑制，将抗辐射细胞转化为辐射敏感细胞。PDOX小鼠的体内功效研究 代表数十名患者的模型将随之而来。 其意义在于，这项工作可能会减少不必要的辐射暴露的病人谁不 保证高剂量颅脊髓照射，确定最适合替代疗法的患者， 并生成临床前数据，以优先考虑即将进行的人体临床试验中最有效的药物。

PROJECT SUMMARY/ABSTRACT I lead the Children’s Oncology Group Phase III clinical trial, ACNS0332, which evaluates treatment options for children with high-risk medulloblastoma (the most common pediatric brain tumor) and supratentorial primitive neuroectodermal tumors (sPNETs). The study opened in 2007 and underwent a major amendment in 2014, when emerging data revealed biological disparity between medulloblastomas and sPNETs as well as heterogeneity in sPNET patients. We discontinued sPNET patient enrollment, and genomic analyses funded by the prior cycle of this grant, revealed that 71% of the non-pineal sPNET patients were actually high grade glioma, ependymoma or atypical teratoid rhabdoid tumors, despite sPNET appearance by histopathology. This reveals the limitations of traditional histopathology and shows that contemporary genomic analyses could spare many children from receiving craniospinal irradiation that is not necessary and not helpful. In Aim 1 of this renewal application, we extend the genomic studies to the 300 medulloblastoma patients in the study. We collected research tissue from over 95% of these patients and anticipate that the studies will reveal 1) patient groups who are likely to die from their disease despite the intense therapy on ACNS0332, 2) patient groups that were placed on ACNS0332 because of clinical or histopathologic observations that may include a mixture of good prognosis patients (e.g., those who would fare well with much less radiation than provided on ACNS0332) as well as those with genomically-predicted poor prognosis, who should be stratified differently in the future. In Aim 2 we address the radiation resistance phenotype of the worst prognosis patients, particularly those with amplified MYC or MYCN. We will collect pre- and post-radiation specimens from patient-derived orthotopic xenograft (PDOX) models (14 MYC/MYCN amplified) that we generated and characterized in the prior cycle of this grant; other PDOX models that we receive from four collaborators; and matching cell lines that we generated and characterized. We will use the cell lines for to screen FDA approved drugs for those that overcome radiation resistance and to conduct functional genomic screens to identify pathways that, when inhibited, convert radiation resistant cells into radiation sensitive cells. In vivo efficacy studies on PDOX mouse models representing dozens of patients will follow. The significance is that this work will likely reduce unnecessary radiation exposure to patients who do not warrant high-dose craniospinal irradiation, identify patients who would best be served by alternative therapies, and generate pre-clinical data to prioritize the most effective agents for upcoming human clinical trials.