The role of Wnt signaling in aggressive thyroid carcinoma
Wnt信号在侵袭性甲状腺癌中的作用
基本信息
- 批准号:10460474
- 负责人:
- 金额:$ 22.95万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-09-01 至 2025-08-31
- 项目状态:未结题
- 来源:
- 关键词:AffectAmerican Cancer SocietyAutomobile DrivingAwardBRAF geneBiologyCell LineClinical TrialsColorectal CancerCombined Modality TherapyCopy Number PolymorphismDataDetectionDevelopmentDiseaseDisease ResistanceEffectivenessEvaluationEvolutionFDA approvedFailureFoundationsFundingGene ExpressionGenetic TranscriptionGoalsGrantGrowthIncidenceKnowledgeLightLinkMEKsMalignant NeoplasmsMalignant neoplasm of thyroidMediatingMedicalMentorsMetastatic/RecurrentMethylationModelingMolecularMusMutationNeoplasm MetastasisOncogenicOrganoidsPapillary thyroid carcinomaPathogenesisPathway interactionsPatientsPharmaceutical PreparationsPhysiciansPlayRecurrenceReporter GenesResearchResearch PersonnelResistanceResourcesRoleSamplingScientistSignal TransductionSystemTestingThyroid GlandThyroid carcinomaUp-RegulationWNT Signaling PathwayWomanWorkanaplastic thyroid cancerbasebeta catenincancer cellcancer diagnosiscancer subtypescohortdriver mutationexome sequencingexperiencegenetic makeupimprovedin vivoinhibitorinhibitor therapymalignant phenotypemouse modelmutantnext generation sequencingnovelnovel therapeuticspatient derived xenograft modelpre-clinicalpreclinical studyprogramsrefractory cancerresistance mechanismstandard of carethyroid neoplasmtranscriptome sequencingtumor
项目摘要
PROJECT SUMMARY:
Thyroid cancer is rapidly increasing in the U.S. and is expected to be the 4th leading cancer diagnosis by 2030,
surpassing colorectal cancer. While most patients are cured of their thyroid cancer following initial treatment, a
significant portion of patients develop recurrent and aggressive disease. In fact, some well-differentiated thyroid
cancers develop into anaplastic thyroid carcinoma (ATC), a highly lethal and treatment-resistant disease with an
abysmal 4-month survival. While these ATCs usually carry common driver-mutations such as BRAFV600E, studies
suggest that the majority also acquire activating mutations in the Wnt pathway. In addition, BRAF inhibitors have
shown limited efficacy in treating these aggressive thyroid tumors. Research in other cancers suggests that Wnt
signaling may play a role in the failure of BRAF inhibitor therapy. There is compelling evidence that thyroid
carcinomas are dependent on Wnt signaling, particularly poorly differentiated and aggressive disease. The goal
of this proposal is to discover the role of Wnt signaling in metastatic, recurrent, and treatment-resistant thyroid
cancer. My preliminary data on BRAFV600E-mutant thyroid cancer demonstrate alterations in Wnt/β-catenin
signaling following BRAF inhibition. My studies also create a unique thyroid cancer organoid system to study
primary patient-derived thyroid cancers across a heterogeneous landscape of genetic alterations. Finally, I
create a humanized patient-derived xenograft mouse model for thyroid cancer, with loss of murine MHCII and
MHCI that can serve to study the in vivo biology of thyroid cancer and to test new therapeutics (including anti-
Wnt drugs) against thyroid cancers resistant to standard-of-care therapy. In this proposal I will test the hypothesis
that Wnt signaling causes the increased invasive and metastatic potential of aggressive thyroid cancer. In Aim
1, I will define the in vivo effect of Wnt inhibition on the malignant phenotype of aggressive thyroid cancer. In Aim
2, I will discover the role of Wnt signaling in the resistance mechanism of BRAF-mutant thyroid cancer following
BRAF inhibitor therapy. In Aim 3, I will use sequential patient samples to determine the drivers of Wnt signaling
upregulation in ATC. Through completion of these studies, I will define the role of Wnt signaling, a major
oncogenic pathway, in thyroid carcinoma. I anticipate that these pre-clinical studies will lead to clinical trials of
Wnt inhibitors for anaplastic thyroid cancer and dramatically improve detection and treatment of the most
aggressive forms of thyroid cancer. In addition, these studies will form the foundation of a strong research
program for a promising junior investigator. Through this K08 grant and the guidance by accomplished mentors,
I will gain the knowledge and experience needed to become an independently funded and successful physician-
scientist.
项目概要:
甲状腺癌在美国迅速增加,预计到2030年将成为第四大癌症诊断,
超过了结肠直肠癌虽然大多数患者在初步治疗后治愈了甲状腺癌,
大部分患者发展为复发性和侵袭性疾病。事实上,一些分化良好的甲状腺
癌症发展成间变性甲状腺癌(ATC),这是一种高度致命和耐药的疾病,
4个月的生存率很低虽然这些ATC通常携带常见的驱动突变,如BRAFV 600 E,但研究表明,
这表明大多数人也获得了Wnt途径中的激活突变。此外,BRAF抑制剂具有
在治疗这些侵袭性甲状腺肿瘤方面表现出有限的疗效。对其他癌症的研究表明,
信号传导可能在BRAF抑制剂治疗失败中起作用。有令人信服的证据表明甲状腺
癌依赖于Wnt信号传导,特别是低分化和侵袭性疾病。目标
这项提议的一个重要目的是发现Wnt信号在转移性、复发性和难治性甲状腺癌中的作用。
癌我关于BRAFV 600 E突变型甲状腺癌的初步数据表明Wnt/β-catenin的改变
BRAF抑制后的信号传导。我的研究还创造了一个独特的甲状腺癌类器官系统来研究
原发性患者源性甲状腺癌的遗传变异的异质景观。最后我
创建甲状腺癌的人源化患者来源的异种移植小鼠模型,其中鼠MHCII缺失,
MHCI可用于研究甲状腺癌的体内生物学,并测试新的治疗方法(包括抗-
Wnt药物)治疗对标准治疗耐药的甲状腺癌。在这份提案中,我将检验
Wnt信号导致侵袭性甲状腺癌的侵袭和转移潜力增加。在Aim中
1,我将定义Wnt抑制对侵袭性甲状腺癌恶性表型的体内影响。在Aim中
2、通过对BRAF突变型甲状腺癌耐药机制的研究,发现Wnt信号通路在BRAF突变型甲状腺癌耐药机制中的作用。
BRAF抑制剂治疗。在目标3中,我将使用连续的患者样本来确定Wnt信号传导的驱动因素
在ATC中上调。通过完成这些研究,我将定义Wnt信号的作用,一个主要的
致癌途径,在甲状腺癌。我预计这些临床前研究将导致临床试验
Wnt抑制剂用于甲状腺未分化癌,并显着改善大多数甲状腺癌的检测和治疗
恶性甲状腺癌此外,这些研究将构成一项强有力的研究的基础
一个有前途的初级调查员的计划通过K 08赠款和有成就的导师的指导,
我将获得成为一名独立资助和成功的医生所需的知识和经验-
科学家
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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Vivian Lee Weiss其他文献
Paediatric thyroid lesions: lessons from recent guidelines
儿科甲状腺病变:近期指南的经验教训
- DOI:
10.1016/s2213-8587(24)00222-5 - 发表时间:
2024-10-01 - 期刊:
- 影响因子:41.800
- 作者:
Esther Diana Rossi;Huiying Wang;Vivian Lee Weiss - 通讯作者:
Vivian Lee Weiss
Vivian Lee Weiss的其他文献
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{{ truncateString('Vivian Lee Weiss', 18)}}的其他基金
The Role of Cancer-Associated Fibroblasts in Thyroid Carcinoma
癌症相关成纤维细胞在甲状腺癌中的作用
- 批准号:
10682554 - 财政年份:2022
- 资助金额:
$ 22.95万 - 项目类别:
The role of Wnt signaling in aggressive thyroid carcinoma
Wnt信号在侵袭性甲状腺癌中的作用
- 批准号:
9976952 - 财政年份:2020
- 资助金额:
$ 22.95万 - 项目类别:
The role of Wnt signaling in aggressive thyroid carcinoma
Wnt信号在侵袭性甲状腺癌中的作用
- 批准号:
10688065 - 财政年份:2020
- 资助金额:
$ 22.95万 - 项目类别:
The role of Wnt signaling in aggressive thyroid carcinoma
Wnt信号在侵袭性甲状腺癌中的作用
- 批准号:
10218118 - 财政年份:2020
- 资助金额:
$ 22.95万 - 项目类别:
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