Diversity Supplement to Targeted Therapy in Ex Vivo Medulloblastoma/PNET

体外髓母细胞瘤/PNET 靶向治疗的多样性补充

• 批准号: 10380520
• 负责人: JAMES M OLSON
• 金额: $ 6.99万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10380520
• 关键词: Address; Alternative Therapies; Amendment; Appearance; Biological; Cell Line; Cells; Child; Childhood Brain Neoplasm; Clinical; Clinical Data; Clinical Trials; Data; Disease; Dose; Ependymoma; Exposure to; FDA approved; Funding; Future; Gene Expression; Genomics; Glioma; Grant; Heterogeneity; Histopathology; Human; Lead; MYCN gene; Mediating; Pathway interactions; Patients; Pediatric Oncology Group; Pharmaceutical Preparations; Phase III Clinical Trials; Phenotype; Primitive Neuroectodermal Tumor; Prognosis; Prognostic Marker; Radiation; Radiation exposure; Research; Rhabdoid Tumor; Specimen; Supratentorial; Supratentorial Neoplasms; Tissues; Work; Xenograft Model; Xenograft procedure; antibody engineering; cancer cell; cell killing; drug candidate; efficacy study; functional genomics; genome wide methylation; high risk; high risk population; in vivo; irradiation; macrophage; medulloblastoma; mouse model; participant enrollment; pre-clinical; radiation resistance; radioresistant; targeted treatment

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.

项目概要/摘要 我领导了儿童肿瘤学组的 III 期临床试验 ACNS0332，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）和幕上原始瘤的儿童 神经外胚层肿瘤（sPNET）。该研究于 2007 年开始，并于 2014 年进行了重大修改， 当新出现的数据揭示了髓母细胞瘤和 sPNET 之间的生物学差异时，以及 sPNET 患者的异质性。当基因组分析获得资助时，我们停止了 sPNET 患者招募 到本次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 神经胶质瘤、室管膜瘤或非典型畸胎瘤样横纹肌样瘤，尽管组织病理学显示有 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且无益的颅脊髓照射。 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 名髓母细胞瘤患者。 学习。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 ACNS0332 进行强化治疗，仍有可能死于疾病的患者群体； 2) 由于临床或组织病理学观察而接受 ACNS0332 治疗的患者组，以及 谁可能包括预后良好的患者（例如，那些在辐射少得多的情况下表现良好的患者） 比 ACNS0332 上提供的），以及基因组预测预后不良的患者，谁应该 未来会有不同的分层。 在目标 2 中，我们解决了预后最差患者的放射抵抗表型，特别是那些患有 扩增 MYC 或 MYCN。我们将从患者来源的原位收集放射前和放射后的标本 我们在前一个周期中生成并表征的异种移植 (PDOX) 模型（14 MYC/MYCN 扩增） 这笔资助，我们从四位合作者那里收到的其他 PDOX 模型，以及我们的匹配细胞系 生成并表征。我们将使用这些细胞系来筛选 FDA 批准的药物，以寻找那些能够克服困难的药物 抗辐射性并进行功能基因组筛选，以确定在受到抑制时， 将抗辐射细胞转化为辐射敏感细胞。 PDOX 小鼠模型的体内功效研究 随后将代表数十名患者。 在多样性补充中，我们仍然关注 MYC/MYCN 扩增的髓母细胞瘤，并使用 相同的 PDOX 系来评估我们设计的多特异性抗体是否可以克服辐射 当局部给药时，耐药性足以诱导巨噬细胞介导的癌细胞杀伤。 意义在于，这项工作可能会减少那些不接受辐射的患者不必要的辐射暴露。 需要高剂量颅脊髓照射，确定最适合接受替代疗法的患者， 并生成临床前数据，以便为即将进行的人体临床试验优先选择最有效的药物。