Establishing MAGE-A4/RAD18 as a novel cancer-specific chemotherapeutic target
将 MAGE-A4/RAD18 确立为新型癌症特异性化疗靶点
基本信息
- 批准号:9905492
- 负责人:
- 金额:$ 40.39万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-04-02 至 2024-03-31
- 项目状态:已结题
- 来源:
- 关键词:AffectAffinityAntigensAntineoplastic AgentsBindingBiological TestingCancer ModelCarcinogenesis MechanismCause of DeathCell SurvivalCellsCellular AssayChemicalsComplexDNA DamageDNA RepairDNA Repair GeneDNA biosynthesisEngineeringEnvironmental Risk FactorGenesGenomic InstabilityGerm CellsGoalsKnowledgeLibrariesLung NeoplasmsMalignant NeoplasmsMalignant neoplasm of lungMissionMitoticMitotic spindleMolecularMutagensNormal CellNude MiceOncogenesOncogenicPathologicPathway interactionsPatientsPeptide Phage Display LibraryPeptidesPermeabilityPhenotypePhysiologicalPlatinumPoisonProblem SolvingProcessProteinsPublic HealthResearchResistanceRoleSignal PathwaySignal TransductionSomatic CellStressStructureTestingTherapeuticTherapeutic AgentsTissuesTopoisomerase IIToxic effectTransgenic MiceUbiquitinUnited States National Institutes of HealthWorkbasecancer cellcancer testis antigencancer therapycarcinogenesischemotherapeutic agentchemotherapydefined contributiondrug discoverydruggable targetenvironmental agentexperienceexperimental studyimprovedin vivoinhibitor/antagonistinnovationmelanomamortalityneoplastic cellnew therapeutic targetnoveloutcome forecastpreclinical studypreneoplastic cellpressurepreventreplication stressresponsescreeningside effectsmall moleculetargeted treatmenttaxanetherapeutic targettherapy resistanttumortumorigenesistumorigenicubiquitin-protein ligase
项目摘要
SUMMARY
There are fundamental gaps in our understanding of how cancer cells acquire DNA damage-tolerance and
evade chemotherapy (termed ‘chemoresistance’). The gaps in our knowledge of DNA damage tolerance (and
how it differs between normal and neoplastic cells), limit our ability to kill tumors without causing side effect
toxicities to normal healthy tissues. Our long-term goals are to solve the problem of how neoplastic cells
tolerate therapy, and identify new molecular vulnerabilities that can be specifically targeted for improved
treatment. The objective here is to define a novel tumor-specific mechanism of chemoresistance and to
establish its tractability as a therapeutic target. Remarkably, we discovered that Melanoma Antigen-A4
(MAGE-A4, a Cancer/Testes Antigen or 'CTA') is an activating binding partner of the DNA repair protein
RAD18 (an E3 ubiquitin ligase). MAGE-A4 is absent from all normal somatic cells but pathologically activates
DNA repair in cancer cells. MAGE-A4 also activates the E3 ligase TRIM69 which confers resistance to mitotic
spindle poisons. MAGE-A4 expression is associated with poor patient prognosis yet its potential impact on the
responsiveness of tumors to chemotherapy in a physiological setting is untested. Based on exciting and
compelling preliminary studies, we will test the central hypothesis that MAGE-A4 pathologically reprograms
ubiquitin signaling in tumors to confer chemoresistance to genotoxins and spindle poisons. The rationale is
that defining the contribution of MAGE-A4 to chemoresistance will allow extraordinarily specific therapeutic
strategies that target a unique molecular vulnerability of neoplastic cells. The Specific Aims are: SA1 Define
contribution of pathologically-activated DNA repair to chemoresistance in vivo. SA2 Establish chemical
tractability of MAGE-A4/RAD18 as a therapeutic target. SA3 Mechanistically define MAGE-A4/TRIM69
functions in mitotic progression and resistance to spindle poisons. In SA1 We will use a new transgenic
mouse and orthotopic lung cancer models to determine how MAGE-A4/RAD18 impacts responses to
chemotherapy in vivo. In SA2 we will screen peptide phage display libraries to identify sequence motifs that
bind MAGE-A4 and disrupt the MAGE-A4/RAD18 interaction. Bioactive MAGE-A4 inhibitor peptides will be
tested for anti-neoplastic activity. In SA3 we will define a novel role of MAGE-A4 in regulating TRIM69 and
conferring resistance to spindle poisons. We will mechanistically define the MAGE-A4/TRIM69 signaling
pathway and establish its role in tolerance of therapeutic taxanes. These experiments will likely establish
MAGE-A4 as a druggable target for ameliorating chemoresistance in cancer cells, serving as a crucial gateway
in the drug discovery process. The proposed ideas and research are innovative because they are the first
studies to test how biological activities of CTAs affect cancer therapy. The proposed work is significant
because it will provide new paradigms for chemoresistance due to pathological ubiquitin signaling leading
directly to novel targeted therapies for chemoresistant cancer.
总结
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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Kenneth Hugh Pearce其他文献
Kenneth Hugh Pearce的其他文献
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{{ truncateString('Kenneth Hugh Pearce', 18)}}的其他基金
Discovery of allosteric activators of phospholipase C-gamma2 to treat Alzheimer's disease
发现用于治疗阿尔茨海默病的磷脂酶 C-gamma2 变构激活剂
- 批准号:
10901007 - 财政年份:2023
- 资助金额:
$ 40.39万 - 项目类别:
A high-throughput platform to identify selective allosteric inhibitors of the PLC-y isozymes
用于鉴定 PLC-y 同工酶选择性变构抑制剂的高通量平台
- 批准号:
10185322 - 财政年份:2021
- 资助金额:
$ 40.39万 - 项目类别:
A high-throughput platform to identify selective allosteric inhibitors of the PLC-y isozymes
用于鉴定 PLC-y 同工酶选择性变构抑制剂的高通量平台
- 批准号:
10399533 - 财政年份:2021
- 资助金额:
$ 40.39万 - 项目类别:
A high-throughput platform to identify selective allosteric inhibitors of the PLC-y isozymes
用于鉴定 PLC-y 同工酶选择性变构抑制剂的高通量平台
- 批准号:
10598548 - 财政年份:2021
- 资助金额:
$ 40.39万 - 项目类别:
Pathological Reprogramming of DNA Damage Signaling in Neoplastic Cells
肿瘤细胞中 DNA 损伤信号的病理重编程
- 批准号:
10530649 - 财政年份:2019
- 资助金额:
$ 40.39万 - 项目类别:
Establishing MAGE-A4/RAD18 as a novel cancer-specific chemotherapeutic target
将 MAGE-A4/RAD18 确立为新型癌症特异性化疗靶点
- 批准号:
10132267 - 财政年份:2019
- 资助金额:
$ 40.39万 - 项目类别:
Establishing MAGE-A4/RAD18 as a novel cancer-specific chemotherapeutic target
将 MAGE-A4/RAD18 确立为新型癌症特异性化疗靶点
- 批准号:
10596489 - 财政年份:2019
- 资助金额:
$ 40.39万 - 项目类别:
Establishing MAGE-A4/RAD18 as a novel cancer-specific chemotherapeutic target
将 MAGE-A4/RAD18 确立为新型癌症特异性化疗靶点
- 批准号:
10363652 - 财政年份:2019
- 资助金额:
$ 40.39万 - 项目类别:
Pathological Reprogramming of DNA Damage Signaling in Neoplastic Cells
肿瘤细胞中 DNA 损伤信号的病理重编程
- 批准号:
10301006 - 财政年份:2019
- 资助金额:
$ 40.39万 - 项目类别:
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