Functional roles of GOF TP53 mutations in metastasis and immunosuppression of head and neck cancers
GOF TP53突变在头颈癌转移和免疫抑制中的功能作用
基本信息
- 批准号:10442206
- 负责人:
- 金额:$ 55.61万
- 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:2022-05-03 至 2027-02-28
- 项目状态:未结题
- 来源:
- 关键词:Alkylating AgentsB-Cell ActivationCellsChromosomal InstabilityComplexCyclic GMPDNADNA biosynthesisDataDevelopmentDiseaseEnhancersGenesGenomic InstabilityGoalsHead and Neck CancerHead and Neck Squamous Cell CarcinomaIL8 geneImmunosuppressionIn VitroIncidenceInflammationInterferonsInterleukin-6KnowledgeLeadLicensing FactorLightLinkMCM5 geneMaintenanceMalignant Epithelial CellMalignant NeoplasmsMediatingMutateMutationMyeloid-derived suppressor cellsNeoplasm MetastasisNuclearPatientsPoly(ADP-ribose) PolymerasesProductionProteinsProteomicsPublic HealthReplication LicensingReportingResearchResistanceRoleSignal TransductionStimulator of Interferon GenesTP53 geneTestingTherapeuticTumor Cell InvasionTumor ImmunityTumor PromotionWorkbasecancer cellcarcinogenesischemokinecytokinecytotoxicitydesigneffective therapygain of functionin vivoinhibitorinnovationmutantnovelnovel therapeutic interventionpreventreplication stressresponsetargeted treatmenttemozolomidetreatment strategytumortumor progressiontumorigenesistumorigenic
项目摘要
Project Summary/Abstract
TP53 is the most common somatically mutated gene among all cancers as it is altered in up to 85% of head and
neck squamous cell carcinomas (HNSCC). Although TP53 mutations often lead to a loss of wild-type p53 (wtp53)
function, many TP53 mutations confer mutant p53 (mutp53) gain-of-function (GOF), promoting cancer cell
genomic instability, proliferation, invasion, metastasis, and cancer inflammation. However, the mechanisms
involved in mutp53 GOF activity remain largely elusive, which is a major obstacle to fully understanding and
targeting mutp53 to prevent tumorigenesis and tumor progression of HNSCC. Our long-term goal is to
understand the role of TP53 mutations in promoting tumorigenesis and tumor progression of HNSCC and to use
this knowledge to develop effective targeted therapies for HNSCC. The objective of this proposed research,
which is the next step in pursuit of that goal, is to identify the specific role of GOF mutp53 in the promotion of
chromosomal instability (CIN), which leads to tumor metastasis and immunosuppression, and to further exploit
this to design novel treatment strategies for HNSCC. Our central hypothesis is that by targeting MCM5, a
component of the replication licensing factor minichromosome maintenance 2-7 complex (MCM2-7), GOF
mutp53 predisposes cells to CIN that leads to a STING-dependent cytosolic DNA response involving
downstream activation of non-canonical nuclear factor kappa light chain enhancer of activated B cell (NF-κB)
signaling, which, in turn, promotes tumor cell invasion, metastasis, and immunosuppression; therefore, targeting
mutp53-mediated signaling can be used as a therapeutic strategy for HNSCC in patients with GOF TP53
mutations. Guided by strong preliminary data, this hypothesis will be tested by pursuing three specific aims: 1)
Determine the functional roles of GOF mutp53-MCM5-cGAS/STING-non-canonical NF-κB signaling in the
promotion of tumor invasion and metastasis in HNSCC cells; 2) Determine the functional roles of GOF mutp53-
MCM5-cGAS/STING-non-canonical NF-κB signaling in the promotion of immunosuppression in HNSCC; 3)
Identify novel therapeutic strategies for HNSCC with GOF p53 mutations. The research proposed in this
application is highly innovative, given that the proposed mechanisms for studying GOF mutant p53 have never
been reported before. Our hypothesis is based on our strong preliminary results from a proteomic screen of the
mutp53 interactome, which uncovered a physical interaction between GOF mutp53 proteins and MCM5. We
expect that the proposed work will identify intrinsic mechanisms of mutp53-mediated GOF in the promotion of
genomic instability, metastasis, and immunosuppression that contribute to tumor development and tumor
progression of HNSCC. Given the high incidence of p53 mutations in HNSCC, the proposed research is expected
to have a significant impact on the public health burden of this deadly disease, and will help us develop novel
therapeutic strategies to treat HNSCC patients with TP53 mutations.
项目总结/摘要
TP 53是所有癌症中最常见的体细胞突变基因,因为它在高达85%的头部和头部肿瘤中发生改变。
颈部鳞状细胞癌(HNSCC)。尽管TP 53突变通常导致野生型p53(wtp 53)的丢失,
由于TP 53的功能,许多TP 53突变赋予突变型p53(mutp 53)功能获得性(GOF),促进癌细胞增殖,
基因组不稳定性、增殖、侵袭、转移和癌症炎症。然而,机制
参与mutp 53 GOF活性主要是难以捉摸的,这是充分理解和
靶向mutp 53以预防HNSCC的肿瘤发生和肿瘤进展。我们的长期目标是
了解TP 53突变在促进HNSCC肿瘤发生和肿瘤进展中的作用,
这一知识,以开发有效的靶向治疗HNSCC。这项研究的目的是,
这是追求这一目标的下一步,是确定GOF mutp 53在促进
染色体不稳定性(CIN),导致肿瘤转移和免疫抑制,并进一步利用
这为HNSCC设计了新的治疗策略。我们的中心假设是,通过靶向MCM 5,
复制许可因子微小染色体维持2-7复合物的组分
mutp 53使细胞易于发生CIN,导致STING依赖性胞质DNA反应,
活化B细胞(NF-κB)非典型核因子κ轻链增强子的下游活化
信号传导,这反过来又促进肿瘤细胞侵袭,转移和免疫抑制;因此,靶向
mutp 53介导的信号传导可用作GOF TP 53患者中HNSCC的治疗策略
突变。在强有力的初步数据的指导下,这一假设将通过追求三个具体目标来检验:
确定GOF mutp 53-MCM 5-cGAS/STING-非经典NF-κB信号传导在细胞凋亡中的功能作用。
促进HNSCC细胞的肿瘤侵袭和转移; 2)确定GOF mutp 53-
MCM 5-cGAS/STING-促进HNSCC中免疫抑制的非经典NF-κB信号传导; 3)
确定GOF p53突变的HNSCC的新治疗策略。这项研究提出,
应用是高度创新的,因为研究GOF突变p53的拟议机制从未
以前报道过。我们的假设是基于我们从蛋白质组学筛选的强有力的初步结果,
mutp 53相互作用组,揭示了GOF mutp 53蛋白和MCM 5之间的物理相互作用。我们
预期所提出的工作将确定mutp 53介导的GOF在促进
基因组不稳定性、转移和免疫抑制导致肿瘤发展和肿瘤
HNSCC的进展。鉴于HNSCC中p53突变的高发生率,预期拟议的研究
对这种致命疾病的公共卫生负担产生重大影响,并将帮助我们开发新的
治疗TP 53突变的HNSCC患者。
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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Jeffrey Nicholas Myers其他文献
Jeffrey Nicholas Myers的其他文献
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{{ truncateString('Jeffrey Nicholas Myers', 18)}}的其他基金
The Houston Center for Acquired Resistance Research (H-CARR)
休斯顿获得性耐药研究中心 (H-CARR)
- 批准号:
10767096 - 财政年份:2022
- 资助金额:
$ 55.61万 - 项目类别:
Functional roles of GOF TP53 mutations in metastasis and immunosuppression of head and neck cancers
GOF TP53突变在头颈癌转移和免疫抑制中的功能作用
- 批准号:
10617289 - 财政年份:2022
- 资助金额:
$ 55.61万 - 项目类别:
The Houston Center for Acquired Resistance Research (H-CARR)
休斯顿获得性耐药研究中心 (H-CARR)
- 批准号:
10830565 - 财政年份:2022
- 资助金额:
$ 55.61万 - 项目类别:
The Houston Center for Acquired Resistance Research (H-CARR)
休斯顿获得性耐药研究中心 (H-CARR)
- 批准号:
10518173 - 财政年份:2022
- 资助金额:
$ 55.61万 - 项目类别:
The Houston Center for Acquired Resistance Research (H-CARR)
休斯顿获得性耐药研究中心 (H-CARR)
- 批准号:
10707142 - 财政年份:2022
- 资助金额:
$ 55.61万 - 项目类别:
Predicting and overcoming chemoradioresistance in p53-mutant head and neck cancer
预测和克服 p53 突变头颈癌的放化疗耐药性
- 批准号:
9281788 - 财政年份:2014
- 资助金额:
$ 55.61万 - 项目类别:
Predicting and overcoming chemoradioresistance in p53-mutant head and neck cancer
预测和克服 p53 突变头颈癌的放化疗耐药性
- 批准号:
8893048 - 财政年份:2014
- 资助金额:
$ 55.61万 - 项目类别:
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