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.

项目总结/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之间的生物学差异时， sPNET患者的异质性。当基因组分析获得资助时，我们停止了sPNET患者入组 由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进行了强烈治疗，但仍可能死于其疾病的患者群体; 和2）由于临床或组织病理学观察结果而接受ACNS 0332治疗的患者组， 其可以包括良好预后患者的混合（例如，那些在辐射少得多的情况下也能活得很好的人 比ACNS 0332提供的更多），以及基因组学预测预后不良的患者， 在未来会有不同的分层。 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， 抗辐射性并进行功能基因组筛选以识别途径，当受到抑制时， 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 代表数十名患者的律师会跟进 在多样性增刊中，我们仍然关注MYC/MYCN扩增的髓母细胞瘤，并使用 同样的PDOX细胞系来评估我们设计的克服辐射的多特异性抗体是否 当局部施用时，抗性足以诱导巨噬细胞介导的癌细胞杀伤。 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。