Diversity Supplement R01CA262388: Overcoming Hypoxic Resistance in Non-Small Cell Lung Cancer By Targeting Mitochondrial Metabolism

多样性补充剂 R01CA262388:通过靶向线粒体代谢克服非小细胞肺癌的缺氧抵抗

基本信息

  • 批准号:
    10595436
  • 负责人:
  • 金额:
    $ 21.63万
  • 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:
    2021-09-22 至 2026-08-31
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY: Many groups are investigating why some lung cancer patients respond well to radio- and immuno-therapies and some do not. One variable is tumor hypoxia, and many groups have shown it can significantly inhibit the effectiveness to these therapeutic modalities. Clinical studies have identified hypoxia as an independent prognostic indicator of poor patient outcomes, but even though this connection has been known for decades, no FDA-approved intervention exists to clinically overcome hypoxia. Some investigators have tried to deliver more oxygen to the tumor, but this approach remains constrained due to the poorly formed tumor vasculature. We have taken an innovative approach and asked if we can reduce demand for, rather than increase supply of, oxygen to reduce hypoxia. We have found that the FDA-approved vasorelaxant papaverine (PPV) has an off- target ability to inhibit mitochondrial complex 1, and reduce oxygen consumption rapidly, in low micromolar concentrations in every cell line tested in vitro. We have also shown that PPV can enhance the effectiveness of radiation and immune checkpoint blockade (ICB) in preclinical models of lung and other cancers, without sensitizing well-oxygenated normal tissue. Reducing hypoxia reverses immune privilege, decreases terminally- exhausted T cells, and increases progenitors that are responsive to PD-1 blockade. We have more recently developed new derivatives of PPV that have lost their vasorelaxant capability and increased their duration of action so that they can be improved immuno-sensitizers. We now propose to test the hypothesis that PPV can effectively enhance the radio- and immuno-therapeutic treatment of preclinical models of lung cancer, and that it is feasible to add PPV to standard of care therapy for advanced non-small cell lung cancer (NSCLC). We have examined TCGA databases and found that lung cancer driver mutations in the KEAP1/NRF2 pathway lead to high levels of mitochondrial gene expression that can cause elevated oxygen metabolism contributing to hypoxia. In Aim 1, we will investigate the effects of oncogenic NRF2 activation human and murine cells and model tumors to determine the dependence of these cells on mitochondrial function, how increased oxygen metabolism contributes to tumor hypoxia, and if therapy-refractory tumors are sensitized by PPV or its derivatives. In Aim 2, we will examine the effect of tumor hypoxia on the migration and activation of T-cells in model tumors and how the immune infiltrate changes after reduction of hypoxia with PPV or its derivatives. Finally, in Aim 3 we will perform a phase 1 clinical trial to determine if the addition of PPV is feasible for patients receiving standard of care chemoradiation followed by immunotherapy for advanced NSCLC. We will look for effectiveness in changing tumor oxygenation using paired blood level oxygen determination (BOLD) MRIs, and for changes in immune populations of peripheral blood mononuclear cells. These studies will let us know if, and how, to use PPV or its novel derivatives in future clinical trials for the treatment of NSCLC.
项目概要:许多小组正在研究为什么一些肺癌患者对无线电反应良好, 免疫疗法和一些没有。其中一个变量是肿瘤缺氧,许多研究小组已经表明, 显著抑制这些治疗方式的有效性。临床研究已经确定缺氧是 是患者预后不良的独立预后指标,但尽管这种联系已经被人们所知, 几十年来,临床上没有FDA批准的干预措施来克服缺氧。一些调查人员试图 向肿瘤输送更多的氧气,但由于肿瘤形成不良, 脉管系统我们采取了一种创新的方法,并询问我们是否可以减少需求,而不是增加 供应氧气以减少缺氧。我们发现FDA批准的血管舒张剂罂粟碱(PPV) 在低微摩尔浓度下, 在体外测试的每个细胞系中的浓度。我们还表明,PPV可以提高有效性, 在肺癌和其他癌症的临床前模型中进行放射和免疫检查点阻断(ICB), 使氧合良好的正常组织敏感。减少缺氧会逆转免疫特权,最终减少- 耗尽的T细胞,并增加对PD-1阻断有反应的祖细胞。我们最近有更多的 开发了PPV的新衍生物,这些衍生物失去了血管舒张能力,并增加了其持续时间。 作用,使它们可以改善免疫增敏剂。我们现在提出检验PPV可以 有效增强肺癌临床前模型的放射和免疫治疗, 在晚期非小细胞肺癌(NSCLC)标准治疗中增加PPV是可行的。我们有 研究了TCGA数据库,发现KEAP 1/NRF 2通路中的肺癌驱动突变导致了 高水平的线粒体基因表达可导致氧代谢升高,从而导致缺氧。 在目的1中,我们将研究致癌NRF 2激活人类和小鼠细胞和模型肿瘤的作用 为了确定这些细胞对线粒体功能的依赖性, 导致肿瘤缺氧,以及治疗难治性肿瘤是否被PPV或其衍生物致敏。在目标2中, 我们将研究肿瘤缺氧对模型肿瘤中T细胞迁移和活化的影响,以及如何影响T细胞的迁移和活化。 PPV或其衍生物减少缺氧后,免疫浸润发生变化。最后,在目标3中, 进行1期临床试验,以确定接受标准PPV治疗的患者是否可行 晚期非小细胞肺癌的护理放化疗后免疫治疗。我们将寻求改变的有效性 使用配对血液水平氧测定(BOLD)MRI的肿瘤氧合,以及免疫组织化学的变化。 外周血单核细胞群。这些研究将让我们知道是否以及如何使用PPV或其 在未来的临床试验中用于治疗NSCLC的新型衍生物。

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)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Nicholas C. Denko其他文献

Hypoxia, HIF1 and glucose metabolism in the solid tumour
实体瘤中的缺氧、HIF1 与葡萄糖代谢
  • DOI:
    10.1038/nrc2468
  • 发表时间:
    2008-08-14
  • 期刊:
  • 影响因子:
    66.800
  • 作者:
    Nicholas C. Denko
  • 通讯作者:
    Nicholas C. Denko
Hypoxic gene expression and metastasis
  • DOI:
    10.1023/b:canc.0000031768.89246.d7
  • 发表时间:
    2004-08-01
  • 期刊:
  • 影响因子:
    8.700
  • 作者:
    Quynh-Thu Le;Nicholas C. Denko;Amato J. Giaccia
  • 通讯作者:
    Amato J. Giaccia

Nicholas C. Denko的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Nicholas C. Denko', 18)}}的其他基金

Overcoming Hypoxic Resistance in Non-Small Cell Lung Cancer By Targeting Mitochondrial Metabolism
通过靶向线粒体代谢克服非小细胞肺癌的缺氧抵抗
  • 批准号:
    10275968
  • 财政年份:
    2021
  • 资助金额:
    $ 21.63万
  • 项目类别:
Overcoming Hypoxic Resistance in Non-Small Cell Lung Cancer By Targeting Mitochondrial Metabolism
通过靶向线粒体代谢克服非小细胞肺癌的缺氧抵抗
  • 批准号:
    10704677
  • 财政年份:
    2021
  • 资助金额:
    $ 21.63万
  • 项目类别:
Overcoming Hypoxic Resistance in Non-Small Cell Lung Cancer By Targeting Mitochondrial Metabolism
通过靶向线粒体代谢克服非小细胞肺癌的缺氧抵抗
  • 批准号:
    10737837
  • 财政年份:
    2021
  • 资助金额:
    $ 21.63万
  • 项目类别:
Overcoming hypoxic resistance to anti-cancer therapy
克服抗癌治疗的缺氧抵抗
  • 批准号:
    10318987
  • 财政年份:
    2020
  • 资助金额:
    $ 21.63万
  • 项目类别:
Overcoming hypoxic resistance to anti-cancer therapy
克服抗癌治疗的缺氧抵抗
  • 批准号:
    10531898
  • 财政年份:
    2020
  • 资助金额:
    $ 21.63万
  • 项目类别:
A phase 0 pilot study to determine if papaverine increases oxygenation in spontaneous canine soft tissue sarcoma
一项 0 期试点研究,以确定罂粟碱是否会增加自发性犬软组织肉瘤的氧合
  • 批准号:
    9985010
  • 财政年份:
    2019
  • 资助金额:
    $ 21.63万
  • 项目类别:
SARRP 200 Small animal radiation research platform
SARRP 200 小动物辐射研究平台
  • 批准号:
    8826303
  • 财政年份:
    2015
  • 资助金额:
    $ 21.63万
  • 项目类别:
Decreasing oxygen metabolism to redcue hypoxia and radiosensitize tumors.
减少氧代谢以减少缺氧并使肿瘤放射增敏。
  • 批准号:
    8700567
  • 财政年份:
    2012
  • 资助金额:
    $ 21.63万
  • 项目类别:
Decreasing oxygen metabolism to redcue hypoxia and radiosensitize tumors.
减少氧代谢以减少缺氧并使肿瘤放射增敏。
  • 批准号:
    8550788
  • 财政年份:
    2012
  • 资助金额:
    $ 21.63万
  • 项目类别:
Decreasing oxygen metabolism to redcue hypoxia and radiosensitize tumors.
减少氧代谢以减少缺氧并使肿瘤放射增敏。
  • 批准号:
    8703638
  • 财政年份:
    2012
  • 资助金额:
    $ 21.63万
  • 项目类别:

相似国自然基金

Neo-antigens暴露对肾移植术后体液性排斥反应的影响及其机制研究
  • 批准号:
    2022J011295
  • 批准年份:
    2022
  • 资助金额:
    10.0 万元
  • 项目类别:
    省市级项目
结核分枝杆菌持续感染期抗原(latency antigens)的重组BCG疫苗研究
  • 批准号:
    30801055
  • 批准年份:
    2008
  • 资助金额:
    19.0 万元
  • 项目类别:
    青年科学基金项目

相似海外基金

Bovine herpesvirus 4 as a vaccine platform for African swine fever virus antigens in pigs
牛疱疹病毒 4 作为猪非洲猪瘟病毒抗原的疫苗平台
  • 批准号:
    BB/Y006224/1
  • 财政年份:
    2024
  • 资助金额:
    $ 21.63万
  • 项目类别:
    Research Grant
Uncovering tumor specific antigens and vulnerabilities in ETP-acute lymphoblastic leukemia
揭示 ETP-急性淋巴细胞白血病的肿瘤特异性抗原和脆弱性
  • 批准号:
    480030
  • 财政年份:
    2023
  • 资助金额:
    $ 21.63万
  • 项目类别:
    Operating Grants
A novel vaccine approach combining mosquito salivary antigens and viral antigens to protect against Zika, chikungunya and other arboviral infections.
一种结合蚊子唾液抗原和病毒抗原的新型疫苗方法,可预防寨卡病毒、基孔肯雅热和其他虫媒病毒感染。
  • 批准号:
    10083718
  • 财政年份:
    2023
  • 资助金额:
    $ 21.63万
  • 项目类别:
    Small Business Research Initiative
Regulation of B cell responses to vaccines by long-term retention of antigens in germinal centres
通过在生发中心长期保留抗原来调节 B 细胞对疫苗的反应
  • 批准号:
    MR/X009254/1
  • 财政年份:
    2023
  • 资助金额:
    $ 21.63万
  • 项目类别:
    Research Grant
Adaptive Discrimination of Risk of Antigens in Immune Memory Dynamics
免疫记忆动态中抗原风险的适应性辨别
  • 批准号:
    22KJ1758
  • 财政年份:
    2023
  • 资助金额:
    $ 21.63万
  • 项目类别:
    Grant-in-Aid for JSPS Fellows
22-ICRAD Call 2 - Improving the diagnosis of tuberculosis in domestic ruminants through the use of new antigens and test platforms
22-ICRAD 呼吁 2 - 通过使用新抗原和测试平台改善家养反刍动物结核病的诊断
  • 批准号:
    BB/Y000927/1
  • 财政年份:
    2023
  • 资助金额:
    $ 21.63万
  • 项目类别:
    Research Grant
Protective immunity elicited by distinct polysaccharide antigens of classical and hypervirulent Klebsiella
经典和高毒力克雷伯氏菌的不同多糖抗原引发的保护性免疫
  • 批准号:
    10795212
  • 财政年份:
    2023
  • 资助金额:
    $ 21.63万
  • 项目类别:
Integrative proteome analysis to harness humoral immune response against tumor antigens
综合蛋白质组分析利用针对肿瘤抗原的体液免疫反应
  • 批准号:
    23K18249
  • 财政年份:
    2023
  • 资助金额:
    $ 21.63万
  • 项目类别:
    Grant-in-Aid for Challenging Research (Exploratory)
Functionally distinct human CD4 T cell responses to novel evolutionarily selected M. tuberculosis antigens
功能独特的人类 CD4 T 细胞对新型进化选择的结核分枝杆菌抗原的反应
  • 批准号:
    10735075
  • 财政年份:
    2023
  • 资助金额:
    $ 21.63万
  • 项目类别:
Targeting T3SA proteins as protective antigens against Yersinia
将 T3SA 蛋白作为针对耶尔森氏菌的保护性抗原
  • 批准号:
    10645989
  • 财政年份:
    2023
  • 资助金额:
    $ 21.63万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了