Defining the role of FAM83B in lung cancer using a new mouse model
使用新的小鼠模型定义 FAM83B 在肺癌中的作用
基本信息
- 批准号:10373095
- 负责人:
- 金额:$ 8.05万
- 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:2021-04-01 至 2023-03-31
- 项目状态:已结题
- 来源:
- 关键词:AblationAutomobile DrivingBindingBiological MarkersCancer cell lineComplexDevelopmentDose-LimitingEpidermal Growth Factor ReceptorEpidermal Growth Factor Receptor Tyrosine Kinase InhibitorEpithelial CellsGenesGenetic ScreeningGenetic TranscriptionGenetically Engineered MouseGoalsHumanHyperplasiaIn VitroKRAS2 geneKnock-outLaboratoriesLungLung AdenocarcinomaMEKsMalignant NeoplasmsMalignant neoplasm of lungMediatingMitogen-Activated Protein KinasesModelingMolecularMouse Cell LineMusMutationNormal CellNormal tissue morphologyOncogenesOncogenicOutcomePartner in relationshipPathway interactionsPatientsPhosphorylationPrecision therapeuticsProtein FamilyProteinsRas InhibitorRas Signaling PathwayRepressionResearchResistanceRoleSignal TransductionTherapeuticToxic effectTumor TissueTumorigenicitycancer cellcancer typecell transformationdrug discoveryexperimental studyforward geneticsin vivoinnovationinsightlung tumorigenesismembermouse modelmutantneoplastic cellnew therapeutic targetnoveloverexpressionpreventprogramsreceptorsmall hairpin RNAsmall molecule inhibitortargeted treatmenttumor growthtumorigenesis
项目摘要
ABSTRACT
RAS signaling is one of the most commonly altered oncogenic pathways in human cancer and one of the most
targeted pathways in drug discovery programs. Yet, while numerous
small molecule inhibitors of RAS effectors
have been identified, the importance of RAS/MAPK signaling in normal tissues and numerous compensatory
signaling mechanisms engaged by cancer cells have prevented their therapeutic utility in many cases. Identifying
new therapeutic targets may help overcome the limitations associated with current precision therapies. The goal
of this proposal is to define the role of the novel oncogene FAM83B, an important RAS/MAPK intermediary, in
driving lung hyperplasia and cancer development in vivo using a newly developed FAM83B mouse model. We
originally identified FAM83B in a forward genetic screen for genes that drive human epithelial cell transformation,
similar to mutant RAS. Our analysis of FAM83B has generated extensive new information about the molecular
functions of FAM83B in cancer cells. We found that elevated FAM83B expression increases RAS/MAPK
signaling, resulting in resistance to a number of targeted therapies. Importantly, inhibition of FAM83B suppresses
RAS/MAPK signaling and reduces tumor growth. FAM83B is significantly elevated in many cancers, including
lung cancer, where it is now recognized as a biomarker in patients with lung adenocarcinoma that have poor
outcomes. Here, we propose to use our innovative new FAM83B mouse model to assess how FAM83B
contributes to lung tumorigenesis in vivo. The objectives of the proposed studies are to: (i) define the role of
FAM83B in driving lung cancer in vivo, alone or in the presence of mutant KRAS, and (ii) determine the FAM83B-
dependent molecular changes in MAPK pathway activation responsible for driving tumorigenesis. While the
proposed studies focus on FAM83B, the impact of our studies is expected to be considerably broader. A second
FAM83 member, FAM83A, was also identified in a forward genetics screen for genes conferring resistance to
EGFR TKIs in transformed HMEC. Importantly, FAM83A and FAM83B are members of an 8 member protein
family, with all FAM83 proteins now shown to activate MAPK signaling in cancer cell lines (via a highly conserved
domain) thereby contributing to tumorigenesis. Thus, our findings using the innovative FAM83B mouse model to
assess how FAM83B contributes to MAPK activation and tumorigenesis in vivo will also inform research into all
FAM83 members, across numerous cancer types.
摘要
RAS信号传导是人类癌症中最常见的改变的致癌途径之一,也是最重要的肿瘤信号传导途径之一。
药物发现计划中的靶向途径。然而,虽然许多
RAS效应子的小分子抑制剂
RAS/MAPK信号在正常组织中的重要性和许多代偿性的
在许多情况下,癌细胞参与的信号传导机制阻碍了它们的治疗效用。识别
新的治疗靶点可能有助于克服与当前精确治疗相关的局限性。目标
这项建议的目的是确定新的癌基因FAM 83 B的作用,FAM 83 B是一种重要的RAS/MAPK中介,
使用新开发的FAM 83 B小鼠模型在体内驱动肺增生和癌症发展。我们
最初在驱动人类上皮细胞转化的基因的正向遗传筛选中鉴定出FAM 83 B,
类似于突变型RAS。我们对FAM 83 B的分析产生了大量关于FAM 83 B分子的新信息。
FAM 83 B在癌细胞中的作用我们发现FAM 83 B表达的增加增加了RAS/MAPK的表达,
信号传导,导致对许多靶向治疗的抗性。重要的是,FAM 83 B的抑制抑制了
RAS/MAPK信号传导和减少肿瘤生长。FAM 83 B在许多癌症中显著升高,包括
肺癌,现在它被认为是肺腺癌患者的生物标志物,
结果。在这里,我们建议使用我们创新的新FAM 83 B小鼠模型来评估FAM 83 B
有助于体内肺肿瘤的发生。拟议研究的目标是:(i)界定
(ii)确定FAM 83 B-突变体KRAS单独或在突变体KRAS存在下在体内驱动肺癌,和
MAPK通路活化中的依赖性分子变化负责驱动肿瘤发生。而
虽然我们提出的研究集中在FAM 83 B上,但我们的研究的影响预计会更广泛。第二
FAM 83成员,FAM 83 A也在正向遗传学筛选中鉴定出赋予对FAM 83的抗性的基因。
转化HMEC中的EGFR TKI。重要的是,FAM 83 A和FAM 83 B是8成员蛋白质的成员
FAM 83家族,所有的FAM 83蛋白现在都显示出在癌细胞系中激活MAPK信号传导(通过高度保守的
域),从而有助于肿瘤发生。因此,我们的研究结果使用创新的FAM 83 B小鼠模型,
评估FAM 83 B如何有助于体内MAPK激活和肿瘤发生也将为所有研究提供信息。
FAM 83成员,跨越多种癌症类型。
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)
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MARK W. JACKSON其他文献
MARK W. JACKSON的其他文献
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{{ truncateString('MARK W. JACKSON', 18)}}的其他基金
Shifting the balance between IFN-I and TGF-beta to improve cancer therapy
改变 IFN-I 和 TGF-β 之间的平衡以改善癌症治疗
- 批准号:
10704231 - 财政年份:2022
- 资助金额:
$ 8.05万 - 项目类别:
Shifting the balance between IFN-I and TGF-beta to improve cancer therapy
改变 IFN-I 和 TGF-β 之间的平衡以改善癌症治疗
- 批准号:
10493939 - 财政年份:2022
- 资助金额:
$ 8.05万 - 项目类别:
Targeting Oncostatin M-Receptor to Suppress Metastasis and Therapy Failure
靶向制瘤素 M 受体抑制转移和治疗失败
- 批准号:
10364703 - 财政年份:2021
- 资助金额:
$ 8.05万 - 项目类别:
Targeting Oncostatin M-Receptor to Suppress Metastasis and Therapy Failure
靶向制瘤素 M 受体抑制转移和治疗失败
- 批准号:
10576854 - 财政年份:2021
- 资助金额:
$ 8.05万 - 项目类别:
Defining the role of FAM83B in lung cancer using a new mouse model
使用新的小鼠模型定义 FAM83B 在肺癌中的作用
- 批准号:
10201807 - 财政年份:2021
- 资助金额:
$ 8.05万 - 项目类别:
Targeting Oncostatin M-Receptor to Suppress Metastasis and Therapy Failure
靶向制瘤素 M 受体抑制转移和治疗失败
- 批准号:
10211081 - 财政年份:2021
- 资助金额:
$ 8.05万 - 项目类别:
Cancer-focused Summer Undergraduate Research (CanSUR) Program
以癌症为重点的暑期本科生研究 (CanSUR) 计划
- 批准号:
10469505 - 财政年份:2018
- 资助金额:
$ 8.05万 - 项目类别:
Cancer-focused Summer Undergraduate Research (CanSUR) Program
以癌症为重点的暑期本科生研究 (CanSUR) 计划
- 批准号:
10678931 - 财政年份:2018
- 资助金额:
$ 8.05万 - 项目类别:
Cancer-focused Summer Undergraduate Research (CanSUR) Program
以癌症为重点的暑期本科生研究 (CanSUR) 计划
- 批准号:
9752503 - 财政年份:2018
- 资助金额:
$ 8.05万 - 项目类别:
Cancer-focused Summer Undergraduate Research (CanSUR) Program
以癌症为重点的暑期本科生研究 (CanSUR) 计划
- 批准号:
10248314 - 财政年份:2018
- 资助金额:
$ 8.05万 - 项目类别:
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