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.
项目概要-项目1:表观遗传学 胰腺导管腺癌(PDA)是一种具有破坏性的疾病,其发病率令人不安地上升。穷人 PDA的预后在很大程度上归因于对常规化疗和免疫治疗的固有抵抗。 治疗来自肿瘤内在和外在表观基因组计划的多因素贡献,一个详细的 肿瘤微环境(TME)内的细胞-细胞通信网络,以及复杂的代谢 适应化合物,使PDA难治目前的武器库的治疗。拟议实验使用 I类组蛋白脱乙酰酶(HDAC)的药理学和遗传靶向,以确定 表观遗传编码程序对治疗抗性的贡献。目标1扩展了实验室的发现 HDAC抑制(HDACi)导致DNA损伤反应途径基因的下调。的能力 HDACi使PDA的类器官和小鼠模型对DNA损伤剂敏感的作用通过使用 一种纳米颗粒递送系统,其在体内规避系统性HDAC抑制剂毒性。鉴于初步 有证据表明HDACi上调自噬(一种已知的治疗耐药性介导剂)、自噬能力 测试了增强对HDACi(以及与DNA损伤剂的组合)的应答的自噬抑制 与项目3合作。此外,对人类类器官库的询问将揭示出 突变谱影响对HDACi和DNA损伤的敏感性。目标2描述了HDAC的贡献- 调节癌症相关成纤维细胞(CAF)中的表观遗传程序,CAF是TME中的一种异质细胞类型, PDA的结果。初步数据确定HDAC 1是CAF反应的主要HDAC, 体外药理学HDACi。在这里,采用遗传方法来确定成纤维细胞中HDAC 1的丢失是如何发生的。 影响CAF功能异质性、肿瘤生长和体内化学抗性。协同努力, 项目2阐明HDACi如何影响肿瘤生长和化疗耐药性的基质支持, CAF衍生的可溶性因子的改变,包括LIF。此外,HDACi的分子机制 在特定的CAF亚群中重新布线表观基因组。最后,目标3建立在初步调查结果的基础上 HDACi使PDA小鼠模型对免疫检查点抑制(ICI)敏感。与项目3合作, HDACi和自噬阻断剂协同促进ICI反应的能力通过会聚的细胞因子而增强。 测试MHC-I的调节。诱导免疫细胞增强抗肿瘤免疫的可能性 还探索了通过HDACi和DNA损伤剂的组合的死亡。协同 项目2,炎症性CAF群体中的STAT信号传导如何影响 定义了HDACi和ICI。最后,为了确定HDACi如何在人类中重新编程免疫调节特征, PDA,来自HDACi和抗PD-1 ICI组合的已完成临床试验的活组织检查通过数字空间分析进行分析。 侧写总之,这些研究提供了关键的见解,表观遗传机制的基础治疗 研究PDA的耐药性,并探索有可能改善患者结局的新治疗策略。

项目成果

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RONALD M EVANS其他文献

RONALD M EVANS的其他文献

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{{ 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:
    8917113
  • 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:
    8921987
  • 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:

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促进癌细胞的抗原呈递,作为 T 细胞免疫治疗的更好靶点
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