Metabolic adaptation enables cisplatin resistance and inhibits tumor immunity

代谢适应使顺铂耐药并抑制肿瘤免疫

基本信息

  • 批准号:
    10518177
  • 负责人:
  • 金额:
    $ 30.6万
  • 依托单位:
  • 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:
    2022-09-20 至 2027-08-31
  • 项目状态:
    未结题

项目摘要

Project 1 SUMMARY A clearer understanding of how tumor cells survive the stress of platinum agents and evolve into therapy resistant populations is essential to overcome treatment failure and maximize both disease control and survival. Our data demonstrate that HNSCC cell lines with acquired cisplatin resistance reduce glycolytic and mitochondrial energy production while increasing carbon flux into anabolic pathways. This results in an enhanced reductive potential (glutathione, NAD(P)H, FADH2) via both glucose and glutamine catabolism coupled to increased glutathione (GS) peroxidase 2 (GPX2) activity coordinated at a genomic and transcriptional level, partially through the KEAP1-NRF2 pathway. Hyperactivation of GPX2 concomitantly likely inhibits NF-κB activation, decreasing chemokine and prostaglandin production by tumor cells— leading to a suppressive tumor immune microenvironment (TIME) enriched for myeloid derived suppressor cells (MDSCs) and depleted of cytotoxic tumor infiltrating lymphocytes (TILs). It is our central hypothesis that this metabolic adaptation is a permissive and required step for acquisition of cisplatin resistance. We further postulate that this metabolic shift transitions some tumors to an immunologically silent phenotype, which reduces immune surveillance to compound the aggressive behavior and cross-therapy resistance of CDDP-treated tumors We will first define the critical metabolic steps required for generation of an enhanced reductive state that supports cisplatin resistance in Aim 1. We will utilize in vitro and in vivo orthotopic HNSCC models to measure the contribution of glucose and glutamine to GS synthesis in cisplatin resistant tumors and, using chemical inhibition coupled to shRNA blockade of individual transporters and enzymes, identify the critical rate limiting metabolic steps for GS synthesis and cisplatin resistance in HNSCC. In Aim 2 we will determine how GS synthesis and utilization (by GPX2 and non GPX means) are coordinated transcriptionally at least in part through Nrf2 in order to support cisplatin resistance. In Aim 3 we will test the impact of GS metabolism via canonical (e.g. NF-kB) and metabolic paracrine signaling on development of a suppressive TIME. Completion of the proposed experiments will: 1) identify suitable targets for ablation of the enhanced reductive state driving cisplatin resistance in HNSCC and 2) identify metabolic biomarkers which can be coupled to 13C flux imaging-based measurements to generate real-time readout of tumor treatment response, and inform a more personalized approach to targeting metabolism to overcome CDDP resistance. By identifying the critical mechanistic underpinnings of metabolic adaptation, we can generate a paradigm shift in our capability to both rapidly detect acquisition of resistance to genotoxic stress and to overcome it using multiple clinically viable approaches. It will further shed light on how acquisition of cisplatin resistance can impact response to immunomodulatory approaches such as immune checkpoint inhibitors (ICIs) currently being combined with chemotherapy in the clinic.
项目1

项目成果

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VLAD C SANDULACHE其他文献

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{{ truncateString('VLAD C SANDULACHE', 18)}}的其他基金

Metabolic adaptation enables cisplatin resistance and inhibits tumor immunity
代谢适应使顺铂耐药并抑制肿瘤免疫
  • 批准号:
    10942977
  • 财政年份:
    2023
  • 资助金额:
    $ 30.6万
  • 项目类别:
Metabolic adaptation enables cisplatin resistance and inhibits tumor immunity
代谢适应使顺铂耐药并抑制肿瘤免疫
  • 批准号:
    10707169
  • 财政年份:
    2022
  • 资助金额:
    $ 30.6万
  • 项目类别:
Improving Treatment Algorithms for Veterans with Oropharyngeal Cancer
改善口咽癌退伍军人的治疗算法
  • 批准号:
    10425236
  • 财政年份:
    2020
  • 资助金额:
    $ 30.6万
  • 项目类别:
Improving Treatment Algorithms for Veterans with Oropharyngeal Cancer
改善口咽癌退伍军人的治疗算法
  • 批准号:
    10152351
  • 财政年份:
    2020
  • 资助金额:
    $ 30.6万
  • 项目类别:
Overcoming cisplatin resistance by targeting fatty acid metabolism
通过靶向脂肪酸代谢克服顺铂耐药性
  • 批准号:
    9980866
  • 财政年份:
    2019
  • 资助金额:
    $ 30.6万
  • 项目类别:
Overcoming cisplatin resistance by targeting fatty acid metabolism
通过靶向脂肪酸代谢克服顺铂耐药性
  • 批准号:
    9795719
  • 财政年份:
    2019
  • 资助金额:
    $ 30.6万
  • 项目类别:

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