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：
10688065
负责人：
Vivian Lee Weiss
金额：
$ 22.95万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
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：
https://reporter.nih.gov/project-details/10688065
关键词：
Affect American Cancer Society Automobile Driving Award BRAF gene Biology Cell Line Clinical Trials Colorectal Cancer Combined Modality Therapy Copy Number Polymorphism Data Detection Development Disease Disease Resistance Effectiveness Evaluation Evolution FDA approved Failure Foundations Funding Gene Expression Genetic Transcription Goals Grant Growth Incidence Knowledge Light Link MEKs Malignant Neoplasms Malignant neoplasm of thyroid Mediating Medical Mentors Methylation Modeling Molecular Mus Mutation Neoplasm Metastasis Oncogenic Organoids Papillary thyroid carcinoma Pathogenesis Pathway interactions Patients Pharmaceutical Preparations Physicians Play Proliferating Recurrence Recurrent disease Reporter Genes Research Research Personnel Resistance Resources Role Sampling Scientist Signal Transduction System Testing Thyroid Gland Thyroid carcinoma Up-Regulation WNT Signaling Pathway Woman Work anaplastic thyroid cancer beta catenin cancer cell cancer diagnosis cancer subtypes cohort driver mutation exome sequencing experience genetic makeup improved in vivo inhibitor inhibitor therapy malignant phenotype mouse model mutant next generation sequencing novel novel therapeutics patient derived xenograft model pre-clinical preclinical study programs refractory cancer resistance mechanism standard of care thyroid neoplasm transcriptome sequencing tumor

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.

项目摘要：甲状腺癌在美国迅速增加，预计到2030年将成为第四次领先的癌症诊断，超直肠癌。虽然大多数患者在初次治疗后都可以治愈其甲状腺癌，但大部分患者会出现复发和侵略性疾病。实际上，一些差异化的甲状腺癌症发展为甲状腺癌癌（ATC），这是一种高度致命和耐药性疾病糟糕的4个月生存。这些ATC通常携带常见的驾驶员 - 武器 - brafv600e，但研究表明大多数还可以在WNT途径中获取激活突变。此外，BRAF抑制剂具有在治疗这些侵袭性甲状腺肿瘤方面的效率有限。其他癌症的研究表明Wnt 信号传导可能在BRAF抑制剂疗法的失败中发挥作用。有令人信服的证据表明甲状腺癌依赖于Wnt信号传导，尤其是分化和侵略性疾病。目标该建议的是发现Wnt信号传导在转移，反复和耐药性甲状腺中的作用癌症。我关于BRAFV600E突变甲状腺癌的初步数据显示Wnt/β-catenin的改变 BRAF抑制后的信号传导。我的研究还创建了独特的甲状腺癌系统来研究原发性患者衍生的甲状腺癌在遗传改变的异质景观中。最后，我为甲状腺癌创建人源化的患者衍生的异种移植小鼠模型，并损失了鼠MHCII和可以研究甲状腺癌的体内生物学并测试新疗法的MHCI WNT药物）针对抗甲状腺癌对护理标准疗法有抵抗力的甲状腺癌。在此提案中，我将检验假设 Wnt信号传导导致侵袭性甲状腺癌的侵入性和转移性潜力增加。目标 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。目标 2，我将发现Wnt信号传导在BRAF突变甲状腺癌的电阻机理中的作用 BRAF抑制剂疗法。在AIM 3中，我将使用顺序的患者样品来确定Wnt信号的驱动因素 ATC上的上调。通过完成这些研究，我将定义Wnt信号的作用，这是一个主要的致癌途径，甲状腺癌。我预计这些临床前研究将导致 WNT抑制剂对甲状腺甲状腺癌的抑制剂，并显着改善了最大的检测和治疗甲状腺癌的侵略性形式。此外，这些研究将构成强大研究的基础有前途的初级调查员的计划。通过这项K08赠款和成熟导师的指导，我将获得成为独立资助和成功的物理学的知识和经验 - 科学家。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Fine-Needle Aspiration Biopsy of Pediatric Salivary Gland Tumors: Analysis of Patient Tolerability, Sedation Requirement, and Procedural Complication.

DOI：
10.1159/000522208
发表时间：
2022
期刊：
Acta cytologica
影响因子：
1.8
作者：
通讯作者：

Evolving approaches in paediatric thyroid cytopathology: A review.

儿科甲状腺细胞病理学方法的演变：综述。

DOI：
10.1111/cyt.13311
发表时间：
2024
期刊：
Cytopathology : official journal of the British Society for Clinical Cytology
影响因子：
0
作者：
Loberg,MatthewA;Tigue,MeganL;Gallant,Jean-Nicolas;Wang,Huiying;Canberk,Sule;Weiss,VivianL
通讯作者：
Weiss,VivianL