Overcoming mechanisms of therapeutic resistance in pancreatic ductal adenocarcinoma

克服胰腺导管腺癌的治疗耐药机制

基本信息

  • 批准号:
    10629062
  • 负责人:
  • 金额:
    $ 295.32万
  • 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 – Overall While mortality rates for many cancers are declining, pancreatic ductal adenocarcinoma (PDA) remains a highly lethal malignancy with the worst 5-year survival rate of the common malignancies. Unfortunately, current therapies are largely ineffective in PDA, an outcome attributed in large part to therapeutic resistance. The highly fibrotic and poorly vascularized tumor microenvironment (TME) restricts both nutrient availability and drug delivery, and provides pro-survival and immunosuppressive cues. These limitations create energy stresses that drive metabolic adaptations to support tumor growth and therapeutic resistance. Moreover, the hyperactivation of pro-survival and resistance pathways in tumor and stromal cell types results in an integrated resistance network. The induction of these pathways is orchestrated by cell-to-cell communications within the TME, including aberrant glycosylation (CA-19-9) and the secretion of immunosuppressive and pro-survival paracrine factors, such as Leukemia Inhibitory Factor (LIF) from cancer-associated fibroblasts (CAFs). In addition, cells adapt to the hypoxic, nutrient-depleted TME by upregulating cell type-specific survival programs, including autophagy. Ultimately, to support and respond to these signaling and metabolic programs, both the tumor and stromal cell epigenomes are reprogrammed, leading to cellular heterogeneity and plasticity that restricts durable therapy responses. Each of these programs promote resistance to a broad range of therapeutics, including chemotherapies, targeted therapies, and immune checkpoint inhibitors. The central hypothesis of this program is that pancreatic cancer has co-opted an integrated network of epigenetic programs, paracrine signaling pathways, and metabolic adaptations to promote tumor survival and therapeutic resistance. Building upon the investigators’ complementary expertise in epigenetics, cell signaling, and metabolic adaptations, as well as common interests in pancreatic cancer, this program seeks to understand the interactions that hinder PDA therapeutic responses, with the ultimate goal of identifying vulnerabilities that can be exploited and targeted to overcome drug resistance. Importantly, the program will utilize advanced mono- and co-culture organoid systems, cutting-edge mouse models, novel therapeutics, single-cell approaches, and human clinical specimens to delineate the contributions of both tumor cells and their stromal support network to therapeutic resistance. Moreover, proposed cooperative and innovative approach will reveal how these resistance nodes are integrated and can be targeted to improve therapeutic outcomes in PDA.
项目总结--总体 虽然许多癌症的死亡率正在下降,但胰腺导管腺癌(Pda)仍然是一种高度危险的疾病。 致命性恶性肿瘤是常见恶性肿瘤中5年生存率最低的。不幸的是,目前 治疗PDA在很大程度上是无效的,这一结果在很大程度上归因于治疗阻力。高度的 纤维化和血运不良的肿瘤微环境(TME)限制了营养物质的供应和药物的使用 传递,并提供有利于生存和免疫抑制的线索。这些限制产生了能量压力, 推动代谢适应,以支持肿瘤生长和治疗耐药性。此外,过度激活 肿瘤和间质细胞类型中的促生存和耐药途径导致整合耐药 网络。这些通路的诱导由TME内的细胞间通信协调, 包括异常糖基化(CA-19-9)和分泌免疫抑制和促进生存的旁分泌 如癌症相关成纤维细胞(CAF)中的白血病抑制因子(LIF)。此外,细胞 通过上调特定细胞类型的生存计划来适应低氧、营养耗竭的TME,包括 自噬。最终,为了支持和响应这些信号和代谢程序,肿瘤和 基质细胞表观基因组被重新编程,导致细胞异质性和可塑性,从而限制了耐用性 治疗反应。这些计划中的每一个都促进了对广泛治疗方法的抵抗,包括 化疗、靶向治疗和免疫检查点抑制剂。 这个项目的中心假设是胰腺癌选择了一个整合的网络 表观遗传程序、旁分泌信号通路和代谢适应促进肿瘤 存活率和治疗耐药性。基于研究人员在表观遗传学方面的互补专业知识, 细胞信号和代谢适应,以及对胰腺癌的共同兴趣,这个项目寻求 了解阻碍PDA治疗反应的相互作用,最终目标是确定 可以利用和有针对性地克服抗药性的漏洞。重要的是,该计划将 利用先进的单一和联合培养器官系统,尖端的小鼠模型,新的治疗方法, 单细胞方法和人类临床标本来描绘肿瘤细胞和其 基质支持网络对治疗耐药。此外,拟议的合作和创新办法将 揭示这些耐药节点是如何整合的,并可以靶向改善PDA的治疗结果。

项目成果

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TONY R. HUNTER其他文献

TONY R. HUNTER的其他文献

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{{ truncateString('TONY R. HUNTER', 18)}}的其他基金

Administrative and Biostatistics Core
行政和生物统计核心
  • 批准号:
    10629066
  • 财政年份:
    2023
  • 资助金额:
    $ 295.32万
  • 项目类别:
Project 2: Targeting signaling networks to overcome therapeutic resistance in pancreatic cancer
项目 2:靶向信号网络克服胰腺癌的治疗耐药性
  • 批准号:
    10629064
  • 财政年份:
    2023
  • 资助金额:
    $ 295.32万
  • 项目类别:
Histidine phosphorylation as a new target for cancer therapy
组氨酸磷酸化作为癌症治疗的新靶点
  • 批准号:
    10680390
  • 财政年份:
    2019
  • 资助金额:
    $ 295.32万
  • 项目类别:
Histidine phosphorylation as a new target for cancer therapy
组氨酸磷酸化作为癌症治疗的新靶点
  • 批准号:
    10228707
  • 财政年份:
    2019
  • 资助金额:
    $ 295.32万
  • 项目类别:
Histidine phosphorylation as a new target for cancer therapy
组氨酸磷酸化作为癌症治疗的新靶点
  • 批准号:
    10020348
  • 财政年份:
    2019
  • 资助金额:
    $ 295.32万
  • 项目类别:
Histidine phosphorylation as a new target for cancer therapy
组氨酸磷酸化作为癌症治疗的新靶点
  • 批准号:
    10450680
  • 财政年份:
    2019
  • 资助金额:
    $ 295.32万
  • 项目类别:
The Invisible Phosphoproteome: New Tools to Study Histidine Phosphorylation
看不见的磷酸化蛋白质组:研究组氨酸磷酸化的新工具
  • 批准号:
    9228357
  • 财政年份:
    2015
  • 资助金额:
    $ 295.32万
  • 项目类别:
The Invisible Phosphoproteome: New Tools to Study Histidine Phosphorylation
看不见的磷酸化蛋白质组:研究组氨酸磷酸化的新工具
  • 批准号:
    9437683
  • 财政年份:
    2015
  • 资助金额:
    $ 295.32万
  • 项目类别:
The Invisible Phosphoproteome: New Tools to Study Histidine Phosphorylation
看不见的磷酸化蛋白质组:研究组氨酸磷酸化的新工具
  • 批准号:
    9017975
  • 财政年份:
    2015
  • 资助金额:
    $ 295.32万
  • 项目类别:
Program Planning
节目策划
  • 批准号:
    8934262
  • 财政年份:
    2013
  • 资助金额:
    $ 295.32万
  • 项目类别:
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