Diversity Supplement to Targeted Therapy in Ex Vivo Medulloblastoma/PNET

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sPNETs之间的生物学差异，以及 SPNET患者的异质性。当基因组分析得到资助时，我们停止了sPNET患者的登记 在这项资助的前一个周期中，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进行了激烈的治疗，但仍有可能死于本病的患者组； 2)因临床或组织病理学观察而放置ACNS0332的患者组 世卫组织可能包括预后良好的患者(例如，那些接受较少放射治疗的患者 ACNS0332)，以及基因预测预后不良的患者，他们应该 在未来进行不同的分层。 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，用于那些 并进行功能基因组筛选，以确定当被抑制时， 将抗辐射细胞转化为辐射敏感细胞。PDOX小鼠模型的体内药效研究 代表数十名患者将紧随其后。 在多样性补充中，我们仍然专注于MYC/MYCN扩增的髓母细胞瘤，并使用 相同的PDOX株来评估我们设计的克服辐射的多特异性抗体 局部给药时，耐药性足以诱导巨噬细胞介导的癌细胞杀伤。 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 when 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 more than 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; and 2) patient groups who were placed on ACNS0332 because of clinical or histopathologic observations and who 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 patients 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 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. In the Diversity Supplement, we remain focused on MYC/MYCN-amplified medulloblastoma and use the same PDOX lines to assess whether a multispecific antibody that we engineered to overcome radiation resistance is sufficient to induce macrophage-mediated cancer cell killing when locally administered. 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.