Targeted Therapy in Ex Vivo Medulloblastoma

离体髓母细胞瘤的靶向治疗

基本信息

批准号：
10531422
负责人：
JAMES M OLSON
金额：
$ 43.87万
依托单位：
SEATTLE CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-01-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10531422
关键词：
Address Adult Alternative Therapies Amendment Appearance Biological Brain Brain Neoplasms Cell Line Cells Child Childhood Childhood Brain Neoplasm Clinical Clinical Data Clinical Trials Clinical Trials Cooperative Group Communities Copy Number Polymorphism Data Diagnosis Disease Disease-Free Survival Dose Enrollment Ependymoma Exposure to FDA approved Funding Future Gene Expression Genetic Genetic Markers Genomics Glioma Goals Grant Heterogeneity Histologic Histopathology Human Intervention Lead MYCN gene Medicine Modeling Molecular Mutation Nature Oncogenic Operative Surgical Procedures Parents Pathway interactions Patient-Focused Outcomes Patients Pediatric Neoplasm Pediatric Oncology Group Pharmaceutical Preparations Pharmacology Phase III Clinical Trials Phenotype Primitive Neuroectodermal Tumor Prognosis Radiation Radiation Dose Unit Radiation exposure Radiation therapy Research Resistance Rhabdoid Tumor Risk Side Specimen Supratentorial Supratentorial Neoplasms Survival Rate Survivors Testing Time Tissues Toxic effect Work Xenograft Model Xenograft procedure base cancer type chemotherapy clinical prognostic drug candidate efficacy study functional genomics genome wide methylation high risk high risk population improved in vivo insight irradiation medulloblastoma mouse model participant enrollment patient derived xenograft model patient prognosis pre-clinical prognostic prognostic indicator radiation resistance radioresistant targeted treatment therapeutic candidate tumor

项目摘要

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.

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 之间的生物学差异以及我们停止了 sPNET 患者的入组，并资助了基因组分析。截至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瘤，尽管组织病理学显示有 sPNET。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美国的 300 名髓母细胞瘤患者。我们收集了超过 95% 的患者的研究组织，并预计研究将揭示这一点。 1) 尽管对 ACNS0332 进行强化治疗，仍可能死于疾病的患者群体，2) 患者由于临床或组织病理学观察而被置于 ACNS0332 的组，这些观察可能包括预后良好的患者的混合体（例如，那些接受比所提供的辐射少得多的治疗的患者） ACNS0332）以及基因组预测预后不良的患者，应根据不同的情况进行不同的分层未来。在目标 2 中，我们解决了预后最差患者的放射抵抗表型，特别是那些患有我们将从患者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获得的其他 PDOX 模型以及我们的匹配细胞系；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，将抗辐射细胞转化为辐射敏感细胞，对 PDOX 小鼠进行体内功效研究。随后将有代表数十名患者的模型。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考虑最有效的药物。