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之间的生物学差异以及 SPNET患者的异质性。我们停止了SPNET患者入学率，并基因组分析资助到这笔赠款的先前周期，有71％的非细细胞SPNET患者实际上是高级神经胶质瘤，室温或非典型霉状类横纹肌肿瘤，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，并预计研究将显示 1）可能死于疾病目的地的患者群体ACNS0332的强烈疗法，2）患者由于可能包括A 良好的预后患者的混合物（例如，那些辐射的辐射效果不佳的人比提供 ACNS0332）以及基因组预测的不良预后的ACNS0332），应分层不同未来。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这笔赠款；我们从四个合作者那里获得的其他PDOX模型；和匹配我们的细胞系生成和表征。我们将使用细胞系来筛选FDA批准的药物克服辐射抗性并进行功能性基因组筛选，以识别当抑制，将抗辐射细胞转化为辐射敏感细胞。 PDOX小鼠的体内效率研究代表数十名患者的模型将随后。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。