In vivo Assessment of Chemotherapy Remodeling of the Bladder Cancer Immune Microenvironment

膀胱癌免疫微环境化疗重塑的体内评估

基本信息

  • 批准号:
    10819107
  • 负责人:
  • 金额:
    $ 7.5万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-08-01 至 2025-04-30
  • 项目状态:
    未结题

项目摘要

ABSTRACT In the United States urothelial carcinoma (UC) of the bladder is the 4th most frequent malignancy in men, and there will be an estimated 80,500 new cases and 17,500 deaths in 2019. Despite being the most costly cancer to treat over a patient’s lifetime, bladder cancer remains underfunded. High-grade (HG), muscle invasive bladder tumors account for the majority of these deaths as patients with metastatic disease have a 5-year survival rate of only 15%. In patients with clinically localized, muscle-invasive bladder cancer (MIBC), there is a high level of evidence to support the use of cisplatin-based neoadjuvant chemotherapy. Two widely accepted regimens with therapeutic equipoise are MVAC (methotrexate, vincristine, adriamycin, and cisplatin) and GC (gemcitabine, cisplatin). While trials in advanced bladder cancer therapy are evaluating the combination of chemo and immunotherapy, to rationally combine these two therapeutic modalities it is imperative to precisely understand how MVAC and GC impact the immune microenvironment and how to best sequence chemo and immunotherapy. Preliminary studies from the Kim and Vincent laboratories show that MVAC and GC have differing effects on the immune microenvironment in bladder cancers of the luminal molecular subtype. Tumors of the luminal subtype, which have low baseline immune infiltration, have a significant increase in immune gene signature expression and clonality of tumor-specific T cell receptor (TCR) clonotypes in the peripheral blood after MVAC but not GC treatment. In contrast, GC significantly increases gene signatures known to promote resistance to IC therapy in bladder cancer (Fibroblast TGFB Response Signature [FTBRS] and EMT-Stroma). These results suggest that in luminal bladder cancers, MVAC promotes an inflamed tumor immune microenvironment permissive to IC inhibition, while GC increases stromal activation, known to correlate with IC resistance. The diversity supplement candidate will leverage a novel, faithful, genetically engineered murine (GEM) model of bladder cancer of the luminal molecular subtype as well as single cell RNA sequencing (scRNAseq) to examine the effect of MVAC and GC at high resolution on the tumor microenvironment. Moreover, he will determine the best sequence of administration of chemo and immunotherapy in these faithful models. The comprehensive career development plan will teach presentation, writing, and networking skills to leverage for the next steps in his career. Successful completion of this scientific work and training program will poise the candidate for a selective, academic post-doctoral fellowship and an effective academic career. 1
摘要

项目成果

期刊论文数量(4)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Collaborative study from the Bladder Cancer Advocacy Network for the genomic analysis of metastatic urothelial cancer.
  • DOI:
    10.1038/s41467-022-33980-9
  • 发表时间:
    2022-11-04
  • 期刊:
  • 影响因子:
    16.6
  • 作者:
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WILLIAM Y. KIM其他文献

WILLIAM Y. KIM的其他文献

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{{ truncateString('WILLIAM Y. KIM', 18)}}的其他基金

Development of a novel biodegradable inorganic nanoparticle therapeutic for cancer
开发一种新型可生物降解的无机纳米颗粒治疗癌症
  • 批准号:
    10651626
  • 财政年份:
    2021
  • 资助金额:
    $ 7.5万
  • 项目类别:
Development of a novel biodegradable inorganic nanoparticle therapeutic for cancer
开发一种新型可生物降解的无机纳米颗粒治疗癌症
  • 批准号:
    10380866
  • 财政年份:
    2021
  • 资助金额:
    $ 7.5万
  • 项目类别:
Chemotherapy and the Bladder Cancer Immune Microenvironment
化疗与膀胱癌免疫微环境
  • 批准号:
    10401438
  • 财政年份:
    2020
  • 资助金额:
    $ 7.5万
  • 项目类别:
Chemotherapy and the Bladder Cancer Immune Microenvironment
化疗与膀胱癌免疫微环境
  • 批准号:
    10222624
  • 财政年份:
    2020
  • 资助金额:
    $ 7.5万
  • 项目类别:
Chemotherapy and the Bladder Cancer Immune Microenvironment
化疗与膀胱癌免疫微环境
  • 批准号:
    10606615
  • 财政年份:
    2020
  • 资助金额:
    $ 7.5万
  • 项目类别:
UNC Integrated Translational Oncology Program (UNC-iTOP)
北卡罗来纳大学综合转化肿瘤学项目 (UNC-iTOP)
  • 批准号:
    10229476
  • 财政年份:
    2019
  • 资助金额:
    $ 7.5万
  • 项目类别:
UNC Integrated Translational Oncology Program (UNC-iTOP)
北卡罗来纳大学综合转化肿瘤学项目 (UNC-iTOP)
  • 批准号:
    10468679
  • 财政年份:
    2019
  • 资助金额:
    $ 7.5万
  • 项目类别:
UNC Integrated Translational Oncology Program (UNC-iTOP)
北卡罗来纳大学综合转化肿瘤学项目 (UNC-iTOP)
  • 批准号:
    10021631
  • 财政年份:
    2019
  • 资助金额:
    $ 7.5万
  • 项目类别:
Kinase Inhibition in Kidney Cancer
肾癌中的激酶抑制
  • 批准号:
    9176328
  • 财政年份:
    2016
  • 资助金额:
    $ 7.5万
  • 项目类别:
Kinase Inhibition in Kidney Cancer
肾癌中的激酶抑制
  • 批准号:
    9752261
  • 财政年份:
    2016
  • 资助金额:
    $ 7.5万
  • 项目类别:
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