Determine the mechanisms of acquired brain-tropism

确定获得性脑向性的机制

基本信息

  • 批准号:
    10813237
  • 负责人:
  • 金额:
    $ 7.64万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-03-01 至 2025-08-31
  • 项目状态:
    未结题

项目摘要

ABSTRACT – PROJECT 1 For patients with advanced cancer, 30% will be afflicted with brain metastases, the cause of devastating neurologic morbidity and mortality. As a result, the incidence of brain metastasis is 170,000 new cases per a year. For screening, MRI is the preferred imaging modality for brain metastasis, but is prohibitively expensive and lacks relevant molecular information. We lack predictive models to identify patients at high risk for brain metastases for screening, as treatment efficacy and morbidity are linked to early detection. Treatment involves surgery and radiotherapy but with a noticeable lack of prognostic or predictive biomarkers for disease progression or treatment. Our central hypothesis is that there are common intrinsic features to the tumor and extrinsic features to the brain microenvironment relevant for cancer brain tropism and response to therapies. We will determine these features’ association to microglia (Project 2) and peripheral immune surveillance (Project 3), leveraging biological models to test these discoveries. We will identify intrinsic cellular genomic features relevant for brain metastasis that can be generalized across many primary tumor types. Likewise, we hypothesize there are extrinsic features of the tumor cellular milieu in the brain that facilitate the seeding and maintenance of these metastases. (1) For determining extrinsic cellular tropism, we will characterize the immune cell types’ states and function in the brain metastasis tumor microenvironment. Using single cell genomics, we will determine the distribution and functional status of the TME microglia and macrophages across different tumor types that have CNS metastasis. In parallel, using three dimensional organoids, we will determine the TME- based macrophage response to anti-CD47, a potent modulator of macrophage function. Our results will determine the cellular genomic characteristics and functional status of TME macrophages/microglial cells and their regulatory states. (2) For intrinsic tropism factors, we will analyze genomic features of the primary tumor and extrinsic features of the brain that indicate increased propensity for brain metastasis. We will conduct genomic sequencing analysis on matched primary and metachronous brain metastasis, with complete treatment exposure patient history. With this data, we will determine critical cancer genome features such as the extent of genomic instability, intratumoral clonal diversity, treatment selection pressure, and TME immune cell composition that are associated with brain metastatic risk. Our results will identify genomic biomarkers indicative of increased risk of brain metastasis across different tumor types. (3) Finally, we will use the overlapping data set for intrinsic genomic factors to determine if there are predictive genomic signatures of radioresistant brain metastases. We hypothesize there are specific genomic features of primary tumors that are radiotherapy predictors. These results may yield potential candidates for increasing sensitivity to this mode of treatment that can be tested in vitro.
摘要-项目1

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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Hanlee P Ji其他文献

Improving bioinformatic pipelines for exome variant calling
  • DOI:
    10.1186/gm306
  • 发表时间:
    2012-01-01
  • 期刊:
  • 影响因子:
    11.200
  • 作者:
    Hanlee P Ji
  • 通讯作者:
    Hanlee P Ji

Hanlee P Ji的其他文献

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{{ truncateString('Hanlee P Ji', 18)}}的其他基金

K-mer indexing for pan-genome reference annotation
用于泛基因组参考注释的 K-mer 索引
  • 批准号:
    10793082
  • 财政年份:
    2023
  • 资助金额:
    $ 7.64万
  • 项目类别:
Integrating cancer genomics and spatial architecture of tumor infiltrating lymphocytes
整合癌症基因组学和肿瘤浸润淋巴细胞的空间结构
  • 批准号:
    10637960
  • 财政年份:
    2023
  • 资助金额:
    $ 7.64万
  • 项目类别:
Single cell modeling of cancer mutations
癌症突变的单细胞建模
  • 批准号:
    10612689
  • 财政年份:
    2023
  • 资助金额:
    $ 7.64万
  • 项目类别:
Project 1 - Molecular and Cellular Determinants of High Risk Gastric Precancerous Lesions
项目1——高危胃癌癌前病变的分子和细胞决定因素
  • 批准号:
    10715762
  • 财政年份:
    2023
  • 资助金额:
    $ 7.64万
  • 项目类别:
Core A: Administrative
核心A:行政
  • 批准号:
    10715765
  • 财政年份:
    2023
  • 资助金额:
    $ 7.64万
  • 项目类别:
Determine the mechanisms of acquired brain-tropism
确定获得性脑向性的机制
  • 批准号:
    10706493
  • 财政年份:
    2021
  • 资助金额:
    $ 7.64万
  • 项目类别:
Determine the mechanisms of acquired brain-tropism
确定获得性脑向性的机制
  • 批准号:
    10272359
  • 财政年份:
    2021
  • 资助金额:
    $ 7.64万
  • 项目类别:
Multimodal iterative sequencing of cancer genomes and single tumor cells
癌症基因组和单个肿瘤细胞的多模式迭代测序
  • 批准号:
    10363694
  • 财政年份:
    2021
  • 资助金额:
    $ 7.64万
  • 项目类别:
Multimodal iterative sequencing of cancer genomes and single tumor cells
癌症基因组和单个肿瘤细胞的多模式迭代测序
  • 批准号:
    10112576
  • 财政年份:
    2021
  • 资助金额:
    $ 7.64万
  • 项目类别:
Determine the mechanisms of acquired brain-tropism
确定获得性脑向性的机制
  • 批准号:
    10927525
  • 财政年份:
    2021
  • 资助金额:
    $ 7.64万
  • 项目类别:

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