Mechanisms of response and resistance to KRAS inhibition in pancreatic cancer

胰腺癌中 KRAS 抑制的反应和耐药机制

基本信息

  • 批准号:
    10566224
  • 负责人:
  • 金额:
    $ 56.18万
  • 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:
    2023-01-01 至 2027-12-31
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY/ABSTRACT Pancreatic ductal adenocarcinoma (PDAC) is a devastating cancer, with a five-year survival of only 10%. There is an urgent need to develop new therapeutic strategies for this disease. Oncogenic KRAS mutations occur in most patients and co-occur with alterations in several different tumor suppressor genes, including TP53, CDKN2A, SMAD4, ARID1A and others. Multiple different transcriptional subtypes of PDAC have also been observed, such as the classical and basal-like programs, which define distinct subsets of disease with differing prognosis and therapeutic response. The recent development of new small molecule inhibitors of KRAS that target KRAS mutations frequently observed in PDAC has the potential to transform the treatment of this disease. We and others have shown that primary and acquired resistance mechanisms can limit the clinical benefit of KRAS inhibitor monotherapy in cancer; thus, understanding the mechanisms of response and resistance to KRAS inhibition in PDAC will be critical to maximize the potential of these therapies. This proposal will use novel mutant-selective KRAS and pan-RAS inhibitors, unique human organoid and mouse models of PDAC, and innovative single-cell and functional genomic approaches to define the genetic, transcriptional and microenvironmental factors that impact response to KRAS inhibition in PDAC. In Aim 1 we will investigate how tumor suppressor genotype can modify response to KRAS inhibition using CRISPR-Cas12a tumor suppressor gene knockout screens in both in vitro and in vivo systems to simultaneously model multiple PDAC genotypes and systematically define genetic biomarkers and mechanisms of sensitivity or resistance to KRAS inhibition. In Aim 2, we will define the role of PDAC transcriptional cell state in modifying response to KRAS inhibition using novel isogenic murine PDAC organoids and human patient-derived PDAC organoids representing the basal-like, classical and neuronal-like subtypes of PDAC. We will characterize subtype-specific adaptive mechanisms of response to KRAS inhibition and evaluate subtype plasticity with a goal to develop combination therapy strategies with KRAS inhibition to target each subtype. In Aim 3, we will build on preliminary single-cell RNA sequencing (scRNA-seq) data from human PDAC biopsies showing that the tumor microenvironment (TME) shapes the transcriptional phenotype and therapeutic response of PDAC cells. We will examine response to oncogenic Kras inhibition in new mouse models of the basal-like, classical and neuronal-like subtypes of PDAC and will interrogate the role of paracrine signaling mechanisms from the TME in modifying malignant cell state and response to KRAS inhibition using ex vivo scRNA-seq and drug sensitivity profiling assays. Collectively, these studies will form a foundation for development of new biomarkers and combination therapies with KRAS inhibition that can be evaluated in future clinical trials for PDAC patients.
项目总结/文摘

项目成果

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Andrew James Aguirre其他文献

Andrew James Aguirre的其他文献

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{{ truncateString('Andrew James Aguirre', 18)}}的其他基金

Stromal modulation of pancreatic cancer malignant cell state and therapeutic sensitivity
胰腺癌恶性细胞状态的基质调节和治疗敏感性
  • 批准号:
    10517569
  • 财政年份:
    2022
  • 资助金额:
    $ 56.18万
  • 项目类别:
Stromal modulation of pancreatic cancer malignant cell state and therapeutic sensitivity
胰腺癌恶性细胞状态的基质调节和治疗敏感性
  • 批准号:
    10706519
  • 财政年份:
    2022
  • 资助金额:
    $ 56.18万
  • 项目类别:
Functional interrogation of epigenetic vulnerabilities in KRAS-mutant pancreatic cancer
KRAS 突变胰腺癌表观遗传脆弱性的功能研究
  • 批准号:
    10221636
  • 财政年份:
    2017
  • 资助金额:
    $ 56.18万
  • 项目类别:
Functional interrogation of epigenetic vulnerabilities in KRAS-mutant pancreatic cancer
KRAS 突变胰腺癌表观遗传脆弱性的功能研究
  • 批准号:
    9370987
  • 财政年份:
    2017
  • 资助金额:
    $ 56.18万
  • 项目类别:

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