Project 1: Overcoming therapeutic resistance in pancreatic cancer through epigenetic reprogramming

项目1:通过表观遗传重编程克服胰腺癌的治疗耐药性

基本信息

  • 批准号:
    10629063
  • 负责人:
  • 金额:
    $ 50.89万
  • 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:
    2023-07-06 至 2028-06-30
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY – Project 1: Epigenetics Pancreatic ductal adenocarcinoma (PDA) is a devastating disease with a disturbing rise in incidence. The poor prognosis of PDA is attributed, in large part, to inherent resistance to conventional chemo- and immuno- therapies. Multifactorial contributions from tumor intrinsic and extrinsic epigenomic programs, an elaborate network of cell-cell communications within the tumor microenvironment (TME), and complex metabolic adaptations compound to make PDA refractory to the current arsenal of therapies. Proposed experiments use both pharmacological and genetic targeting of Class I histone deacetylases (HDACs) to determine the contributions of epigenetically encoded programs to therapeutic resistance. Aim 1 expands on the lab’s finding that HDAC inhibition (HDACi) leads to a downregulation of DNA damage response pathway genes. The ability of HDACi to sensitize both organoid and mouse models of PDA to DNA damaging agents is tested by employing a nanoparticle delivery system that circumvents systemic HDAC inhibitor toxicities in vivo. Given preliminary evidence that HDACi upregulates autophagy, a known mediator of therapeutic resistance, the ability of autophagy inhibition to potentiate responses to HDACi (and combinations with DNA damaging agents) is tested in collaboration with Project 3. Moreover, interrogation of a human organoid bank will delineate how different mutational profiles impact sensitivities to HDACi and DNA damage. Aim 2 delineates the contribution of HDAC- regulated epigenetic programs in cancer-associated fibroblasts (CAFs), a heterogenous cell type within the TME, to PDA outcomes. Preliminary data identifies HDAC1 as the primary HDAC underlying CAF responses to pharmacological HDACi in vitro. Here, a genetic approach is taken to determine how HDAC1 loss in fibroblasts impacts CAF functional heterogeneity, tumor growth, and chemoresistance in vivo. Collaborative efforts with Project 2 elucidate how HDACi influences stromal support of tumor growth and chemoresistance through alterations in CAF-derived soluble factors, including LIF. In addition, the molecular mechanisms by which HDACi rewires the epigenome in specific CAF subpopulations is delineated. Lastly, Aim 3 builds on preliminary findings that HDACi sensitizes PDA mouse models to immune checkpoint inhibition (ICI). In collaboration with Project 3, the ability of HDACi and autophagy blockade to synergize in promoting ICI responses through convergent regulation of MHC-I is tested. The possibility of enhancing anti-tumor immunity by inducing immunological cell death through the combination of HDACi and DNA damaging agents is also explored. In collaboration with Project 2, how STAT signaling in inflammatory CAF populations influences anti-tumor immunity elicited by HDACi and ICI is defined. Finally, to determine how HDACi reprograms immunomodulatory features in human PDA, biopsies from a completed clinical trial combining HDACi and anti-PD-1 ICI are analyzed via digital spatial profiling. Together, these studies provide critical insight into the epigenetic mechanisms underlying therapeutic resistance in PDA and explore novel treatment strategies with the potential to improve patient outcomes.
项目摘要--项目1:表观遗传学 胰腺导管腺癌(PDA)是一种破坏性疾病,其发病率有令人不安的上升趋势。穷人 PDA的预后在很大程度上归因于对传统化疗和免疫耐药的固有抵抗。 治疗。肿瘤内在和外在表观基因组计划的多因素贡献 肿瘤微环境(TME)内的细胞-细胞通讯网络和复杂的代谢 适应化合物,使PDA难以应对目前的治疗方法。拟议的实验使用 I类组蛋白脱乙酰酶(HDAC)的药理和基因靶向研究 表观遗传编码程序对治疗耐药的贡献。目标1对实验室的发现进行了扩展 HDAC抑制(HDACi)导致DNA损伤反应通路基因下调。一种能力 HDACi使器官和小鼠模型的PDA对DNA损伤剂增敏的试验是通过使用 一种在体内规避全身HDAC抑制剂毒性的纳米颗粒递送系统。已给出初步结果 HDACi上调自噬的证据表明,自噬是治疗耐药的已知媒介,其能力 测试自噬抑制以增强对HDACi(以及与DNA损伤剂的组合)的反应 与项目3合作。此外,对人类器官库的审问将描绘出 突变特征会影响对HDACi和DNA损伤的敏感性。目标2描述了人类发展援助中心的贡献-- 癌相关成纤维细胞(CAF)中受调控的表观遗传程序,CAF是TME中的一种异源细胞类型, 对PDA结果的影响。初步数据表明,HDAC1是CAF反应的主要HDAC基础 体外药理HDACi。在这里,采用遗传学方法来确定成纤维细胞中HDAC1的丢失 影响CAF功能异质性、肿瘤生长和体内化疗耐药性。与以下公司合作 项目2阐明HDACi如何通过以下途径影响肿瘤生长的间质支持和化疗耐药性 CAF衍生的可溶性因子的改变,包括LIF。此外,HDACI的分子机制 重新连接了特定CAF亚群中的表观基因组。最后,目标3建立在初步结果的基础上 HDACi使PDA小鼠模型对免疫检查点抑制(ICI)敏感。在与项目3的合作下, HDACi和自噬阻断在促进ICI反应中的协同作用 对MHC-I的调节进行了测试。诱导免疫细胞增强抗肿瘤免疫的可能性 还探讨了通过HDACi和DNA损伤剂的组合造成的死亡。与 项目2,炎症性CAF人群中的STAT信号如何影响由 定义了HDACi和ICI。最后,为了确定HDACi如何重新编程人类的免疫调节功能 PDA,来自HDACI和抗PD-1 ICI的完整临床试验的活检组织通过数字空间分析 侧写。总之,这些研究为治疗的表观遗传机制提供了重要的洞察力。 PDA的耐药性,并探索有可能改善患者预后的新治疗策略。

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 }}

RONALD M EVANS其他文献

RONALD M EVANS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('RONALD M EVANS', 18)}}的其他基金

Tissue-specific roles of FXR in CVD and NASH
FXR 在 CVD 和 NASH 中的组织特异性作用
  • 批准号:
    10461065
  • 财政年份:
    2020
  • 资助金额:
    $ 50.89万
  • 项目类别:
Tissue-specific roles of FXR in CVD and NASH
FXR 在 CVD 和 NASH 中的组织特异性作用
  • 批准号:
    10262919
  • 财政年份:
    2020
  • 资助金额:
    $ 50.89万
  • 项目类别:
Tissue-specific roles of FXR in CVD and NASH
FXR 在 CVD 和 NASH 中的组织特异性作用
  • 批准号:
    10683976
  • 财政年份:
    2020
  • 资助金额:
    $ 50.89万
  • 项目类别:
Engineering human islet-like organoids for transplantation
工程化人类胰岛样器官用于移植
  • 批准号:
    10161781
  • 财政年份:
    2018
  • 资助金额:
    $ 50.89万
  • 项目类别:
Engineering human islet-like organoids for transplantation
工程化人类胰岛样器官用于移植
  • 批准号:
    9788431
  • 财政年份:
    2018
  • 资助金额:
    $ 50.89万
  • 项目类别:
Expansion of NURSA Transcriptomine Annotation
NURSA 转录组注释的扩展
  • 批准号:
    9102645
  • 财政年份:
    2012
  • 资助金额:
    $ 50.89万
  • 项目类别:
A Hub for the Nuclear Receptor Signaling Atlas1
核受体信号图谱的枢纽1
  • 批准号:
    8921987
  • 财政年份:
    2012
  • 资助金额:
    $ 50.89万
  • 项目类别:
BD2K: INTEROPERABILITY OF NURSA WITH PHARMGKB AND DKNET
BD2K:NURSA 与 PARMGKB 和 DKNET 的互操作性
  • 批准号:
    9057203
  • 财政年份:
    2012
  • 资助金额:
    $ 50.89万
  • 项目类别:
A Hub for the Nuclear Receptor Signaling Atlas1
核受体信号图谱的枢纽1
  • 批准号:
    8917113
  • 财政年份:
    2012
  • 资助金额:
    $ 50.89万
  • 项目类别:
A Hub for the Nuclear Receptor Signaling Atlas1
核受体信号图谱的枢纽1
  • 批准号:
    8546381
  • 财政年份:
    2012
  • 资助金额:
    $ 50.89万
  • 项目类别:

相似海外基金

Defining MHC class I restricted antigen presentation to CD8 T cells in experimental AD and Tauopathy - Supplement
定义实验性 AD 和 Tau 病中 MHC I 类限制性抗原呈递至 CD8 T 细胞 - 补充
  • 批准号:
    10836880
  • 财政年份:
    2023
  • 资助金额:
    $ 50.89万
  • 项目类别:
Targeting MAL2-mediated endocytosis to enhance tumor cell antigen presentation
靶向 MAL2 介导的内吞作用以增强肿瘤细胞抗原呈递
  • 批准号:
    10734324
  • 财政年份:
    2023
  • 资助金额:
    $ 50.89万
  • 项目类别:
Antigen presentation to the adaptive immune system in the choroid contributes to ocular autoimmune disease
脉络膜中的适应性免疫系统的抗原呈递导致眼部自身免疫性疾病
  • 批准号:
    10740465
  • 财政年份:
    2023
  • 资助金额:
    $ 50.89万
  • 项目类别:
Investigation of Target Protein Degradation and Its Effect on Enhancing Cancer-Specific Antigen Presentation by Quantitative Mass Spectrometry
通过定量质谱研究靶蛋白降解及其对增强癌症特异性抗原呈递的影响
  • 批准号:
    23K04971
  • 财政年份:
    2023
  • 资助金额:
    $ 50.89万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Promoting cancer cells' antigen presentation for serving as better targets for T cell immunotherapy
促进癌细胞的抗原呈递,作为 T 细胞免疫治疗的更好靶点
  • 批准号:
    2885451
  • 财政年份:
    2023
  • 资助金额:
    $ 50.89万
  • 项目类别:
    Studentship
Targeting immunoproteasome-mediated antigen presentation in colorectal cancer immunotherapy
结直肠癌免疫治疗中靶向免疫蛋白酶体介导的抗原呈递
  • 批准号:
    10385926
  • 财政年份:
    2022
  • 资助金额:
    $ 50.89万
  • 项目类别:
Lipid Antigen Presentation as a Driver of T2D Inflammation
脂质抗原呈递作为 T2D 炎症的驱动因素
  • 批准号:
    10509043
  • 财政年份:
    2022
  • 资助金额:
    $ 50.89万
  • 项目类别:
Enhancing antigen presentation in triple negative breast cancers through CD40 agonist, Flt3 ligand, and anthracycline chemotherapy
通过 CD40 激动剂、Flt3 配体和蒽环类化疗增强三阴性乳腺癌的抗原呈递
  • 批准号:
    10704008
  • 财政年份:
    2022
  • 资助金额:
    $ 50.89万
  • 项目类别:
Sex Differences in lipid antigen presentation, impact of lipid antigen presentation on peripheral lipid metabolism
脂质抗原呈递的性别差异,脂质抗原呈递对外周脂质代谢的影响
  • 批准号:
    10818273
  • 财政年份:
    2022
  • 资助金额:
    $ 50.89万
  • 项目类别:
Enhancing antigen presentation in triple negative breast cancers through CD40 agonist, Flt3 ligand, and anthracycline chemotherapy
通过 CD40 激动剂、Flt3 配体和蒽环类化疗增强三阴性乳腺癌的抗原呈递
  • 批准号:
    10349397
  • 财政年份:
    2022
  • 资助金额:
    $ 50.89万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了