Targeted Therapy in Ex Vivo Medulloblastoma

项目摘要/摘要 我领导儿童肿瘤学小组第三阶段临床试验，ACNS0332，该试验评估治疗方案 儿童高危髓母细胞瘤(最常见的儿童脑肿瘤)和幕上原始肿瘤 神经外胚层肿瘤(SPNETs)。这项研究于2007年开始，并在2014年进行了重大修改， 当新出现的数据显示髓母细胞瘤和sPNET之间的生物学差异以及 SPNET患者的异质性。我们停止了sPNET患者的登记，并资助了基因组分析 在这项资助的前一个周期，显示71%的非松果体sPNET患者实际上是高级别的 胶质瘤、室管膜瘤或不典型的畸胎样横纹肌样肿瘤，尽管组织病理学显示为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 让许多儿童免于接受不必要也没有帮助的颅脑脊髓照射。 在这次更新应用的目标1中，我们将基因组研究扩展到300名髓母细胞瘤患者。 学习。我们收集了超过95%的这些患者的研究组织，并预计研究将揭示 1)尽管对ACNS0332患者进行了密集治疗，但仍有可能死于他们的疾病的患者组，2)患者 因临床或组织病理学观察而放置在ACNS0332上的组，可能包括 预后良好的患者的混合(例如，那些接受比所提供的辐射少得多的放射治疗的患者 ACNS0332)以及基因预测预后不良的患者，他们的分层应该不同 未来。 在目标2中，我们讨论了预后最差的患者的辐射抵抗表型，特别是那些 扩增的MYC或MYCN。我们将从患者来源的原位标本中收集放射治疗前后的样本。 异种移植(PDOX)模型(14个MYC/MYCN扩增)，我们在上一个周期中生成并表征了 这笔赠款；我们从四个合作者那里获得的其他PDOX模型；以及我们匹配的细胞系 生成并表征的。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，将耐辐射细胞转化为辐射敏感细胞。PDOX小鼠体内药效研究 代表数十名患者的模特将效仿。 重要的是，这项工作可能会减少不必要的辐射暴露给那些没有 保证高剂量的颅脑照射，确定哪些患者最适合接受替代疗法， 并生成临床前数据，为即将到来的人类临床试验确定最有效的药物的优先顺序。

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.