Combinatorial Targeting of Epigenomic and Microenvironmental Pathways to Suppress MAPK Inhibitor Resistance in Melanoma

表观基因组和微环境途径的组合靶向抑制黑色素瘤中 MAPK 抑制剂耐药性

基本信息

  • 批准号:
    10189526
  • 负责人:
  • 金额:
    $ 37.05万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2013
  • 资助国家:
    美国
  • 起止时间:
    2013-08-07 至 2024-06-30
  • 项目状态:
    已结题

项目摘要

ABSTRACT Mutation-targeted small molecular inhibitors and immune checkpoint antibodies have extended the quality and quantity of life for patients with advanced MUTBRAF melanoma. Development of combinations based on these foundational therapies should yield further survival benefits in the near future. The combo of BRAF and MEK inhibitors specifically suppresses a form of resistance driven mainly by genetic alterations that result in MAPK- reactivation and restoration of MAPK-addiction. However, this clinically validated approach to suppress BRAF inhibitor resistance does not address epigenomic and immunologic alterations that drive resistance via MAPK- redundant and CD8 T-cell-depleted tumor states. We propose to uncover combinatorial targets in advanced V600BRAF mutant melanoma by understanding MAPK inhibitor-induced epigenomic and immune-suppressive mechanisms and their interplay. We hypothesize that MAPK inhibitor-induced tumor cell-intrinsic and extrinsic adaptations, which have been linked to innate anti-PD-1 resistance, converge on the elaboration and actions of TGFβ, BMP, or VEGFA in the tumor immune microenvironment. The Lo Lab has a track record of integrating analysis of clinical and experimental resistance evolution to derive translatable preclinical strategies to suppress resistance. We propose (Aim 1) to generate a landscape perspective of epigenome-directed tumor cell-intrinsic resistance evolution by comparative analysis of human melanoma cell lines, patient-derived xenografts and immune-competent murine melanoma models. This analysis seeks to identify master transcriptional factors regulating phenotypic transitions to provide insights into resistance-regulatory growth factors and signaling pathways. In Aim 2, we will test the hypothesis that MAPK inhibitors induce adaptive epigenomic and immune-suppressive processes via elaboration of specific TGFβs or BMPs. The action of these factors on the tumor cells and the tumor microenvironment will be analyzed, respectively, by characterization of cis-regulatory enhancer or super-enhancer modules involving TGFβ/BMP receptor-regulated SMADs and by single-cell RNA-seq of dissociated tumors. In Aim 3, we will evaluate the efficacy and mechanisms of blocking TGFβ, BMP, or VEGFA on top of the MAPKi+aPD-L1 foundation and dissect the influence of the most efficacious combination on single T-cell clonotypes and epigenetic states of activation or exhaustion. Together, these studies will advance translation of our understanding of multi-faceted resistance mechanisms into next-generation combinatorial therapies for advanced melanoma.
抽象的 针对突变的小分子抑制剂和免疫检查点抗体延长了治疗的质量和 晚期 MUTBRAF 黑色素瘤患者的生命质量。在此基础上开发组合 基础疗法应该会在不久的将来带来更多的生存益处。 BRAF 和 MEK 的组合 抑制剂专门抑制一种主要由基因改变驱动的耐药性,导致 MAPK- MAPK 成瘾的重新激活和恢复。然而,这种经过临床验证的抑制 BRAF 的方法 抑制剂耐药性并不能解决通过 MAPK- 驱动耐药性的表观基因组和免疫学改变 冗余和 CD8 T 细胞耗尽的肿瘤状态。我们建议提前发现组合目标 通过了解 MAPK 抑制剂诱导的表观基因组和免疫抑制来了解 V600BRAF 突变黑色素瘤 机制及其相互作用。我们假设 MAPK 抑制剂诱导的肿瘤细胞具有内在和外在的作用 与先天性抗 PD-1 耐药性相关的适应,集中于以下因素的阐述和行动: 肿瘤免疫微环境中的 TGFβ、BMP 或 VEGFA。 Lo 实验室拥有整合临床和实验耐药性进化分析的记录,以得出 抑制耐药性的可转化临床前策略。我们建议(目标 1)生成景观 通过比较分析人类表观基因组导向的肿瘤细胞内在耐药性进化的视角 黑色素瘤细胞系、患者来源的异种移植物和免疫活性小鼠黑色素瘤模型。本次分析 旨在识别调节表型转变的主要转录因子,以提供对以下方面的见解 耐药调节生长因子和信号通路。在目标 2 中,我们将检验 MAPK 的假设 抑制剂通过特定 TGFβ 的阐述诱导适应性表观基因组和免疫抑制过程或 BMP。将分析这些因素对肿瘤细胞和肿瘤微环境的作用, 分别通过涉及 TGFβ/BMP 的顺式调节增强子或超级增强子模块的表征 受体调节的 SMAD 和分离肿瘤的单细胞 RNA-seq。在目标 3 中,我们将评估 在 MAPKi+aPD-L1 基础上阻断 TGFβ、BMP 或 VEGFA 的功效和机制,以及 剖析最有效的组合对单个 T 细胞克隆型和表观遗传状态的影响 激活或耗尽。总之,这些研究将促进我们对多方面理解的转化 晚期黑色素瘤的下一代组合疗法的耐药机制。

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 }}

ROGER S LO其他文献

ROGER S LO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('ROGER S LO', 18)}}的其他基金

Core 1: Mouse Model and Tissue Biobank Core
核心 1:小鼠模型和组织生物库核心
  • 批准号:
    10526106
  • 财政年份:
    2022
  • 资助金额:
    $ 37.05万
  • 项目类别:
Core 1: Mouse Model and Tissue Biobank Core
核心 1:小鼠模型和组织生物库核心
  • 批准号:
    10708931
  • 财政年份:
    2022
  • 资助金额:
    $ 37.05万
  • 项目类别:
Understanding PD-L1/L2 protein regulation, detection and signaling to predict melanoma therapeutic sensitivity
了解 PD-L1/L2 蛋白调控、检测和信号传导以预测黑色素瘤治疗敏感性
  • 批准号:
    10358524
  • 财政年份:
    2021
  • 资助金额:
    $ 37.05万
  • 项目类别:
Project 1: Strategies to enhance MEK inhibitor efficacy in MUTNRAS melanoma
项目 1:增强 MEK 抑制剂对 MUTNRAS 黑色素瘤疗效的策略
  • 批准号:
    10261396
  • 财政年份:
    2020
  • 资助金额:
    $ 37.05万
  • 项目类别:
Project 1: Strategies to enhance MEK inhibitor efficacy in MUTNRAS melanoma
项目 1:增强 MEK 抑制剂对 MUTNRAS 黑色素瘤疗效的策略
  • 批准号:
    10443859
  • 财政年份:
    2020
  • 资助金额:
    $ 37.05万
  • 项目类别:
Project 1: Strategies to enhance MEK inhibitor efficacy in MUTNRAS melanoma
项目 1:增强 MEK 抑制剂对 MUTNRAS 黑色素瘤疗效的策略
  • 批准号:
    10025136
  • 财政年份:
    2020
  • 资助金额:
    $ 37.05万
  • 项目类别:
Combinatorial Targeting of Epigenomic and Microenvironmental Pathways to Suppress MAPK Inhibitor Resistance in Melanoma
表观基因组和微环境途径的组合靶向抑制黑色素瘤中 MAPK 抑制剂耐药性
  • 批准号:
    10439777
  • 财政年份:
    2013
  • 资助金额:
    $ 37.05万
  • 项目类别:
Combinatorial Targeting of Epigenomic and Microenvironmental Pathways to Suppress MAPK Inhibitor Resistance in Melanoma
表观基因组和微环境途径的组合靶向抑制黑色素瘤中 MAPK 抑制剂耐药性
  • 批准号:
    9912727
  • 财政年份:
    2013
  • 资助金额:
    $ 37.05万
  • 项目类别:
Overcoming acute, adaptive BRAF inhibitor resistance in melanoma
克服黑色素瘤中急性、适应性 BRAF 抑制剂耐药性
  • 批准号:
    8595186
  • 财政年份:
    2013
  • 资助金额:
    $ 37.05万
  • 项目类别:
Overcoming acute, adaptive BRAF inhibitor resistance in melanoma
克服黑色素瘤中急性、适应性 BRAF 抑制剂耐药性
  • 批准号:
    9283342
  • 财政年份:
    2013
  • 资助金额:
    $ 37.05万
  • 项目类别:

相似海外基金

Rational design of rapidly translatable, highly antigenic and novel recombinant immunogens to address deficiencies of current snakebite treatments
合理设计可快速翻译、高抗原性和新型重组免疫原,以解决当前蛇咬伤治疗的缺陷
  • 批准号:
    MR/S03398X/2
  • 财政年份:
    2024
  • 资助金额:
    $ 37.05万
  • 项目类别:
    Fellowship
CAREER: FEAST (Food Ecosystems And circularity for Sustainable Transformation) framework to address Hidden Hunger
职业:FEAST(食品生态系统和可持续转型循环)框架解决隐性饥饿
  • 批准号:
    2338423
  • 财政年份:
    2024
  • 资助金额:
    $ 37.05万
  • 项目类别:
    Continuing Grant
Re-thinking drug nanocrystals as highly loaded vectors to address key unmet therapeutic challenges
重新思考药物纳米晶体作为高负载载体以解决关键的未满足的治疗挑战
  • 批准号:
    EP/Y001486/1
  • 财政年份:
    2024
  • 资助金额:
    $ 37.05万
  • 项目类别:
    Research Grant
Metrology to address ion suppression in multimodal mass spectrometry imaging with application in oncology
计量学解决多模态质谱成像中的离子抑制问题及其在肿瘤学中的应用
  • 批准号:
    MR/X03657X/1
  • 财政年份:
    2024
  • 资助金额:
    $ 37.05万
  • 项目类别:
    Fellowship
CRII: SHF: A Novel Address Translation Architecture for Virtualized Clouds
CRII:SHF:一种用于虚拟化云的新型地址转换架构
  • 批准号:
    2348066
  • 财政年份:
    2024
  • 资助金额:
    $ 37.05万
  • 项目类别:
    Standard Grant
The Abundance Project: Enhancing Cultural & Green Inclusion in Social Prescribing in Southwest London to Address Ethnic Inequalities in Mental Health
丰富项目:增强文化
  • 批准号:
    AH/Z505481/1
  • 财政年份:
    2024
  • 资助金额:
    $ 37.05万
  • 项目类别:
    Research Grant
ERAMET - Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
ERAMET - 快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
  • 批准号:
    10107647
  • 财政年份:
    2024
  • 资助金额:
    $ 37.05万
  • 项目类别:
    EU-Funded
BIORETS: Convergence Research Experiences for Teachers in Synthetic and Systems Biology to Address Challenges in Food, Health, Energy, and Environment
BIORETS:合成和系统生物学教师的融合研究经验,以应对食品、健康、能源和环境方面的挑战
  • 批准号:
    2341402
  • 财政年份:
    2024
  • 资助金额:
    $ 37.05万
  • 项目类别:
    Standard Grant
Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
  • 批准号:
    10106221
  • 财政年份:
    2024
  • 资助金额:
    $ 37.05万
  • 项目类别:
    EU-Funded
Recite: Building Research by Communities to Address Inequities through Expression
背诵:社区开展研究,通过表达解决不平等问题
  • 批准号:
    AH/Z505341/1
  • 财政年份:
    2024
  • 资助金额:
    $ 37.05万
  • 项目类别:
    Research Grant
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了