Targeting cell regulatory states to complement MEK/autophagy inhibition in pancreatic cancer

靶向细胞调节状态以补充胰腺癌中的 MEK/自噬抑制

基本信息

  • 批准号:
    10587719
  • 负责人:
  • 金额:
    $ 56.41万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-12-19 至 2027-11-30
  • 项目状态:
    未结题

项目摘要

Abstract Pancreatic ductal adenocarcinoma (PDAC) is characterized by its broad, primary resistance to genotoxic chemotherapy, targeted therapy, and immunotherapy. The singular driving oncogene of PDAC is KRAS, which is mutated in 95% of cases. Unfortunately, inhibitors of the specific mutant KRAS alleles found in PDAC are not yet clinically available, and all attempts to target downstream effector pathways have been stymied by feedback loops and other resistance mechanisms. Work from our collaborators found that inhibition of the MEK pathway, a key KRAS effector, results in compensatory upregulation of autophagy, a survival pathway. Combination MEK and autophagy inhibition was shown to have synergistic effects in reducing viability of PDAC cell lines and led to tumor responses in model systems and individual case reports from human patients. However, only a subset of patients have responded to MEK/autophagy inhibitors in early clinical trials. Among those who respond, most tumors progress within a few months. Nevertheless, this is potentially the first example of an active regimen lacking genotoxic agents. Published mechanisms for the synergy between MEK and autophagy inhibitors in PDAC do not readily explain the rapid emergence of resistance, do not account for cellular heterogeneity within the malignant epithelial compartment, and do not address the role of the tumor stroma in the response to therapy. The overall goal of this proposal is take a holistic approach to understanding cellular responses to MEK/autophagy inhibition by studying the effects of treatment on every cell type in the tumor. We will do this by performing single cell RNA sequencing and analyzing the data using single cell regulatory network analysis – an advanced computational framework designed to systematically measure the activity of every transcription factor in each individual cell. This innovative new approach enables us both to identify specific cellular subtypes impacted by treatment, and to rapidly identify the mechanistic drivers of observed responses. We will deploy this approach on tumor samples from four different model systems: genetically engineered (KPC) mice, human patient derived xenografts (PDXs), patient-derived tumor “explant” models (freshly cultured intact tissue slices), and samples from an active clinical trial of MEK/autophagy inhibition in PDAC patients. Extensive preliminary data in human cell lines, human PDAC explants, and KPC mouse tumors demonstrate that MEK/autophagy inhibition primarily impacts specific subsets of three major cell types: epithelial cells, fibroblasts, and macrophage/monocytes. Our three aims will study the effects and mechanisms of MEK/autophagy inhibition in each cell type, with the goals of annotating phenotypes, learning whether effects are cell autonomous, determining the transcription factors driving treatment response, understanding impacts on the remaining cells, and identifying new therapeutic combinations to potentiate anticancer effects.
摘要 胰腺导管腺癌(PDAC)的特点是其广泛的,原发性耐药的遗传毒性, 化疗、靶向治疗和免疫治疗。PDAC的单一驱动癌基因是KRAS, 在95%的情况下都发生了变异不幸的是,在PDAC中发现的特定突变KRAS等位基因的抑制剂, 尚未临床可用,并且所有靶向下游效应物途径的尝试都受到以下因素的阻碍: 反馈回路和其他阻力机制。 我们的合作者的工作发现,抑制MEK途径,一个关键的KRAS效应,导致 自噬的补偿性上调,这是一种生存途径。MEK和自噬抑制的组合是 显示在降低PDAC细胞系的存活力方面具有协同作用,并导致模型中的肿瘤应答 系统和人类患者的个体病例报告。然而,只有一小部分患者有反应 MEK/自噬抑制剂的早期临床试验。在那些有反应的人中,大多数肿瘤在一周内进展。 几个月然而,这可能是第一个缺乏遗传毒性药物的活性方案的例子。 已发表的PDAC中MEK和自噬抑制剂之间协同作用的机制尚不容易解释。 解释耐药性的快速出现,不能解释恶性肿瘤内的细胞异质性。 上皮区室,并且没有解决肿瘤基质在对治疗的反应中的作用。的 该提案的总体目标是采取整体方法来理解细胞对MEK/自噬的反应 通过研究治疗对肿瘤中每种细胞类型的影响来抑制肿瘤。我们将通过表演 单细胞RNA测序和使用单细胞调控网络分析来分析数据-一种 先进的计算框架,旨在系统地测量每个转录的活动 每个细胞中的因子。这种创新的新方法使我们能够识别特定的细胞 受治疗影响的亚型,并快速识别观察到的反应的机制驱动因素。我们将 将这种方法应用于来自四种不同模型系统的肿瘤样品:遗传工程(KPC)小鼠, 人患者来源的异种移植物(PDX)、患者来源的肿瘤“外植体”模型(新鲜培养的完整组织 切片),以及来自PDAC患者中MEK/自噬抑制的有效临床试验的样品。 人细胞系、人PDAC外植体和KPC小鼠肿瘤的大量初步数据 证明MEK/自噬抑制主要影响三种主要细胞类型的特定亚群: 上皮细胞、成纤维细胞和巨噬细胞/单核细胞。我们的三个目标将研究的影响和机制 MEK/自噬抑制在每种细胞类型,与注释表型的目标,学习是否 作用是细胞自主的,决定驱动治疗反应的转录因子,理解 对剩余细胞的影响,并确定新的治疗组合,以加强抗癌效果。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Gulam Abbas Manji其他文献

Gulam Abbas Manji的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Gulam Abbas Manji', 18)}}的其他基金

Elucidation and targeting of paracrine cascades in PDAC
PDAC 中旁分泌级联的阐明和靶向
  • 批准号:
    10518098
  • 财政年份:
    2022
  • 资助金额:
    $ 56.41万
  • 项目类别:
Phase 2 study of combination therapy with PLX3397 and sirolimus to target tumor-associated macrophages in malignant peripheral nerve sheath tumors
PLX3397和西罗莫司联合治疗恶性周围神经鞘肿瘤中肿瘤相关巨噬细胞的2期研究
  • 批准号:
    10364636
  • 财政年份:
    2017
  • 资助金额:
    $ 56.41万
  • 项目类别:
Phase 2 study of combination therapy with PLX3397 and sirolimus to target tumor-associated macrophages in malignant peripheral nerve sheath tumors
PLX3397和西罗莫司联合治疗恶性周围神经鞘肿瘤中肿瘤相关巨噬细胞的2期研究
  • 批准号:
    9444352
  • 财政年份:
    2017
  • 资助金额:
    $ 56.41万
  • 项目类别:

相似海外基金

Establishment of a method for evaluating automobile driving ability focusing on frontal lobe functions and its application to accident prediction
以额叶功能为中心的汽车驾驶能力评价方法的建立及其在事故预测中的应用
  • 批准号:
    20K07947
  • 财政年份:
    2020
  • 资助金额:
    $ 56.41万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Evaluation of the Effectiveness of Multi-Professional Collaborative Assessment of Cognitive Function and Automobile Driving Skills and Comprehensive Support
认知功能与汽车驾驶技能多专业协同评估效果评价及综合支持
  • 批准号:
    17K19824
  • 财政年份:
    2017
  • 资助金额:
    $ 56.41万
  • 项目类别:
    Grant-in-Aid for Challenging Research (Exploratory)
Development of Flexible Automobile Driving Interface for Disabled People
残疾人灵活汽车驾驶界面开发
  • 批准号:
    25330237
  • 财政年份:
    2013
  • 资助金额:
    $ 56.41万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Automobile driving among older people with dementia: the effect of an intervention using a support manual for family caregivers
患有痴呆症的老年人的汽车驾驶:使用家庭护理人员支持手册进行干预的效果
  • 批准号:
    23591741
  • 财政年份:
    2011
  • 资助金额:
    $ 56.41万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了