Proj 3 - Targeting the Pro-tumorigenic Microenvironment

项目 3 - 针对促肿瘤微环境

基本信息

  • 批准号:
    10265474
  • 负责人:
  • 金额:
    $ 55.57万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2017
  • 资助国家:
    美国
  • 起止时间:
    2017-09-18 至 2023-12-31
  • 项目状态:
    已结题

项目摘要

SUMMARY/ABSTRACT The overall objective of Project 4 is to discover and exploit extrinsic mechanisms of therapy resistance by focusing on the contribution of tumor-associated macrophages (TAMs) and tumor-associated fibroblasts (TAFs) in the tumor microenvironment (TME). Our overarching hypothesis is that TAMs and TAFs cooperate in creating a favorable tumorigenic environment that ultimately leads to the emergence of therapeutic resistance and immune escape in NB. We also postulate that as tumors are treated, the TME is altered in its composition and function to become increasingly favorable to therapeutic resistance. This hypothesis is based on published and preliminary data from our group demonstrating that TAMs and TAFs are abundantly present in an inflammatory subtype of NB at diagnosis associated with a high risk of recurrence and extremely poor prognosis. We also have evidence that TAMs and TAFs when exposed to tumor cells stimulate their proliferation, survival and drug-resistance via the paracrine production of pro-tumorigenic cytokines and chemokines that activate in tumor cells signaling pathways such as STAT3 and ERK. Our project has 3 aims. Aim 1, will examine mechanisms of cooperation between TAMs and TAFs, testing the hypothesis that in MYCN amplified tumors that do not produce the TAM chemoattractant CCL-2/MCP-1, TAFs are a source of this chemokine. We will also examine the contribution of cytokines and chemokines generated in co-culture of TAMs, TAFs and NB cells and the signaling pathways they activate in NB cells leading to increased proliferation and survival. Aim 2, will examine changes in the TME landscape secondary to chemotherapy in syngeneic murine NB models (with Project 2) and validate the data in patient tumor samples obtained via Core B. By examining changes in the transcriptome that occur in NB cells chronically exposed to TAM/TAF and their potential epigenetic origin (with Project 3), aim 2 will also identify vulnerabilities to prevent resistance to chemotherapy or targeted therapy (with Project 1). Aim 3, will then translate these discoveries in pre-clinical tumor models. We will test the therapeutic efficacy of the most promising agents targeting TAFs, TAMs, or pathways they activate in tumor cells in combination with chemotherapy or immunotherapy (with Project 5), using human NB lines and patient-derived xenotransplants in immunodeficient mice as well as murine cell lines in immunocompetent mice (with Project 2), The most effective agent(s) will then be proposed for early phase clinical trials to the NANT (Core B). Thus Project 4 brings a unique contribution to the overall objective of this PPG through its focus on the TME and on non-autonomous mechanisms leading towards therapeutic resistance and immune escape.
摘要/文摘

项目成果

期刊论文数量(0)
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会议论文数量(0)
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Yves A DeClerck其他文献

SEPTICEMIA IN CHILDREN WITH LEUKEMIA: A TEN-YEAR SURVEY
白血病患儿败血症:一项十年调查
  • DOI:
    10.1203/00006450-198704010-00780
  • 发表时间:
    1987-04-01
  • 期刊:
  • 影响因子:
    3.100
  • 作者:
    Josette Champagne;Yves A DeClerck
  • 通讯作者:
    Yves A DeClerck

Yves A DeClerck的其他文献

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{{ truncateString('Yves A DeClerck', 18)}}的其他基金

Exosomes in tumor cell-mesenchymal stromal cell interaction
肿瘤细胞-间充质基质细胞相互作用中的外泌体
  • 批准号:
    10177876
  • 财政年份:
    2017
  • 资助金额:
    $ 55.57万
  • 项目类别:
Proj 3 - Targeting the Pro-tumorigenic Microenvironment
项目 3 - 针对促肿瘤微环境
  • 批准号:
    10017936
  • 财政年份:
    2017
  • 资助金额:
    $ 55.57万
  • 项目类别:
AACR Special Conference on Tumor Microenvironment Complexity: Emerging Roles in C
AACR 肿瘤微环境复杂性特别会议:C 中的新兴角色
  • 批准号:
    8257077
  • 财政年份:
    2011
  • 资助金额:
    $ 55.57万
  • 项目类别:
Center for Environment-Mediated Drug Resistance in Pediatric Cancer
环境介导的小儿癌症耐药性中心
  • 批准号:
    8727485
  • 财政年份:
    2011
  • 资助金额:
    $ 55.57万
  • 项目类别:
Center for Environment-Mediated Drug Resistance in Pediatric Cancer
环境介导的小儿癌症耐药性中心
  • 批准号:
    8213000
  • 财政年份:
    2011
  • 资助金额:
    $ 55.57万
  • 项目类别:
Administrative Core
行政核心
  • 批准号:
    8555324
  • 财政年份:
    2011
  • 资助金额:
    $ 55.57万
  • 项目类别:
Center for Environment-Mediated Drug Resistance in Pediatric Cancer
环境介导的小儿癌症耐药性中心
  • 批准号:
    8335415
  • 财政年份:
    2011
  • 资助金额:
    $ 55.57万
  • 项目类别:
Targeting IL-6/IL-6R/STAT3 in EMDR in Neuroblastoma
神经母细胞瘤 EMDR 中靶向 IL-6/IL-6R/STAT3
  • 批准号:
    8555321
  • 财政年份:
    2011
  • 资助金额:
    $ 55.57万
  • 项目类别:
Center for Environment-Mediated Drug Resistance in Pediatric Cancer
环境介导的小儿癌症耐药性中心
  • 批准号:
    8548303
  • 财政年份:
    2011
  • 资助金额:
    $ 55.57万
  • 项目类别:
Fifth International Conference on Tumor Microenvironment: Progression, Therapy a
第五届国际肿瘤微环境会议:进展、治疗
  • 批准号:
    7804830
  • 财政年份:
    2009
  • 资助金额:
    $ 55.57万
  • 项目类别:
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