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

基本信息

  • 批准号:
    10380520
  • 负责人:
  • 金额:
    $ 6.99万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

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 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/文摘

项目成果

期刊论文数量(0)
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JAMES M OLSON其他文献

JAMES M OLSON的其他文献

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{{ truncateString('JAMES M OLSON', 18)}}的其他基金

Targeted Therapy in Ex Vivo Medulloblastoma
离体髓母细胞瘤的靶向治疗
  • 批准号:
    10531422
  • 财政年份:
    2022
  • 资助金额:
    $ 6.99万
  • 项目类别:
Engineering Knotted Peptide Therapeutics for Pediatric Brain Tumor Patients
针对小儿脑肿瘤患者的工程打结肽治疗
  • 批准号:
    10531428
  • 财政年份:
    2022
  • 资助金额:
    $ 6.99万
  • 项目类别:
Targeted Therapy in Ex Vivo Medulloblastoma
离体髓母细胞瘤的靶向治疗
  • 批准号:
    10560551
  • 财政年份:
    2022
  • 资助金额:
    $ 6.99万
  • 项目类别:
Targeted Therapy in Ex Vivo Medulloblastoma
离体髓母细胞瘤的靶向治疗
  • 批准号:
    10738311
  • 财政年份:
    2022
  • 资助金额:
    $ 6.99万
  • 项目类别:
Engineering knotted peptide therapeutics for pediatric brain tumor patients
为儿童脑肿瘤患者设计打结肽疗法
  • 批准号:
    9897193
  • 财政年份:
    2019
  • 资助金额:
    $ 6.99万
  • 项目类别:
Combinations of Synergistic Bispecific Human Antibodies: A Novel Strategy for the Treatment of Neuroblastoma
协同双特异性人类抗体的组合:治疗神经母细胞瘤的新策略
  • 批准号:
    10228852
  • 财政年份:
    2018
  • 资助金额:
    $ 6.99万
  • 项目类别:
Engineering knotted peptide therapeutics for pediatric brain tumor patients
为儿童脑肿瘤患者设计打结肽疗法
  • 批准号:
    10083110
  • 财政年份:
    2018
  • 资助金额:
    $ 6.99万
  • 项目类别:
Sideport Needle Array Technologies for Prioritizing Drugs for Cancer Patients
用于优先考虑癌症患者药物的侧端口针阵列技术
  • 批准号:
    8294620
  • 财政年份:
    2011
  • 资助金额:
    $ 6.99万
  • 项目类别:
Infant and Toddler Brain Tumors
婴儿和幼儿脑肿瘤
  • 批准号:
    8848786
  • 财政年份:
    2011
  • 资助金额:
    $ 6.99万
  • 项目类别:
Infant and Toddler Brain Tumors
婴儿和幼儿脑肿瘤
  • 批准号:
    8455703
  • 财政年份:
    2011
  • 资助金额:
    $ 6.99万
  • 项目类别:

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