Defining the KRAS mutation specific interactions in pancreas cancer

定义胰腺癌中 KRAS 突变的特异性相互作用

基本信息

  • 批准号:
    10529253
  • 负责人:
  • 金额:
    $ 22.51万
  • 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:
    2021-08-11 至 2024-07-31
  • 项目状态:
    已结题

项目摘要

Pancreatic cancer is characterized by mutational activation of the “undruggable” KRAS proto-oncogene, and approximately 95% of all pancreatic ductal adenocarcinoma (PDAC) patients harbor a KRAS mutation. With an abysmal five-year survival rate of 10%, developing effective therapeutic strategies remains a high priority. The KRASG12D mutation represents the most common KRAS mutation in PDAC followed by KRASG12V and KRASG12R. However, other mutations, such as KRASQ61L, are non-existent in PDAC despite being highly oncogenic in model systems. Thus, KRAS mutations are not equal, and each mutant may regulate distinct as well as overlapping signaling pathways. We will map the protein interactions of specific KRAS mutants utilizing both 2D and 3D cell models. In Aim 1, we will employ a new version of Biotin Identification (BioID) proximity ligation assays, termed TurboID, to define the mutation-specific protein interactions. My work on KRASG12R provides an excellent example of KRAS mutation-specific signaling. We hypothesize that the mutant-specific effector interactions in KRAS-initiated PDAC will illuminate which pathways are most susceptible to therapeutic disruption. In Aim 2, we propose to expand the Cell Models Core of the CDLD to generate mouse- and patient-derived pancreatic organoids for use in our studies and others at MUSC. KRAS signaling varies depending on whether cells are grown on plastic (2D) vs 3D environments. To address this complexity, we will extend our BioID studies into 3D organoids developed from normal mouse pancreas. This approach will allow for the use of a “normal” organoid line to define the mutation-specific signaling differences between KRAS mutants. The use of normal mouse organoids will allow for an isogenic “normal” environment that is more representative of the natural pancreas environment in which KRAS initiates the early stages of pancreatic cancer. To validate whether the mutation-selective effector pathways are necessary in an early cancer model system, we will establish pre-neoplastic organoids from KrasLSL-G12D/+ and KrasLSL-G12R/+ mouse models, where the KRAS mutation is expressed in the native gene locus to validate the potential targets. This approach will help define a new class of mutation-specific therapies in pancreatic cancer.
胰腺癌的特点是“不可治疗的”KRAS原癌基因的突变激活,

项目成果

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Guy Hobbs其他文献

Guy Hobbs的其他文献

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{{ truncateString('Guy Hobbs', 18)}}的其他基金

Defining the KRAS mutation specific interactions in pancreas cancer
定义胰腺癌中 KRAS 突变的特异性相互作用
  • 批准号:
    10531847
  • 财政年份:
    2020
  • 资助金额:
    $ 22.51万
  • 项目类别:
Defining the KRAS mutation specific interactions in pancreas cancer
定义胰腺癌中 KRAS 突变的特异性相互作用
  • 批准号:
    10586129
  • 财政年份:
    2020
  • 资助金额:
    $ 22.51万
  • 项目类别:

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  • 批准号:
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