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.
项目概述-整体

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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