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.

项目摘要/摘要 我领导儿童肿瘤学组III期临床试验ACNS0332，该试验评估了治疗方案 具有高危髓母细胞瘤（最常见的小儿脑肿瘤）和象征性原始的儿童 神经外科肿瘤（SPNET）。这项研究于2007年开业，并于2014年进行了重大修正案， 当新兴数据揭示了髓母细胞瘤和SPNET之间的生物差异时， SPNET患者的异质性。当基因组分析资助时，我们停止了SPNET患者入学率 到这笔赠款的先前周期表明，有71％的非细细胞SPNET患者实际上是高级的 神经胶质瘤，室心症或非典型畸胎组织横纹肌肿瘤，组织病理学出现Dospite 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 免除许多孩子没有必要且无济于事的颅骨脊髓照射。 在此更新应用的AIM 1中，我们将基因组研究扩展到300名髓母细胞瘤患者 学习。我们从这些患者中有95％以上收集了研究组织，并预计研究将会 揭示：1）可能因其疾病目的地死亡的患者群体在ACNS0332上进行了严格的治疗； 2）由于临床或组织病理学观察，被置于ACNS0332上的患者组 谁可能包括良好的预后患者的混合物（例如，那些辐射率较少的人 比ACNS0332）以及基因组预测的不良预后的患者应该是 将来对不同的分层分层。 在AIM 2中，我们解决了最严重的预后患者的辐射抗性表型，尤其是患有 放大了MYC或MYCN。我们将从患者衍生的原位收集放射和后放射标本 异种移植（PDOX）模型（14个MYC/MYCN扩增），我们在先前的周期中生成和表征 我们从四个合作者那里获得的其他PDOX模型，以及我们匹配的单元线 生成和表征。我们将使用细胞系来筛选FDA批准的药物 辐射阻力和进行功能性基因组筛选，以识别抑制时的途径 将抗辐射细胞转化为辐射敏感细胞。 PDOX小鼠模型的体内效率研究 代表数十名患者。 在多样性补充中，我们仍然专注于MYC/MYCN放大的髓母细胞瘤，并使用 相同的PDOX线以评估我们设计以克服辐射的多特异性抗体 耐药性足以诱导局部给药时巨噬细胞介导的癌细胞杀死。 意义在于，这项工作可能会减少不必要的辐射暴露于 认证高剂量颅骨脊髓辐照，确定最好通过替代疗法服务的患者， 并生成临床前数据，以优先考虑即将进行的人类临床试验的最有效的药物。