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
• 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
• 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/10218118
• 关键词: Affect; American Cancer Society; Anaplastic Carcinomas; 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; Metastatic/Recurrent; Methylation; Modeling; Molecular; Mus; Mutation; Neoplasm Metastasis; Oncogenic; Organoids; Papillary thyroid carcinoma; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Physicians; Play; Recurrence; 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; base; beta catenin; cancer cell; cancer diagnosis; cancer subtypes; cohort; driver mutation; exome sequencing; experience; genetic makeup; improved; in vivo; inhibitor/antagonist; 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

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： 甲状腺癌在美国正在迅速增加，预计到 2030 年将成为第四大癌症诊断， 超越结直肠癌。虽然大多数患者的甲状腺癌经过初步治疗后即可治愈，但 很大一部分患者会出现复发性和侵袭性疾病。事实上，一些分化良好的甲状腺 癌症发展为甲状腺未分化癌 (ATC)，这是一种高度致命且难以治疗的疾病， 糟糕的4个月生存率。虽然这些 ATC 通常携带常见的驱动突变，例如 BRAFV600E，但研究 表明大多数人还获得了 Wnt 通路的激活突变。此外，BRAF抑制剂具有 在治疗这些侵袭性甲状腺肿瘤方面显示出有限的疗效。对其他癌症的研究表明 Wnt 信号传导可能是 BRAF 抑制剂治疗失败的原因之一。有令人信服的证据表明甲状腺 癌症依赖于 Wnt 信号传导，尤其是低分化和侵袭性疾病。目标 该提案的目的是发现 Wnt 信号在转移性、复发性和难治性甲状腺中的作用 癌症。我关于 BRAFV600E 突变型甲状腺癌的初步数据表明 Wnt/β-连环蛋白发生了变化 BRAF 抑制后的信号转导。我的研究还创建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跨越异质的遗传改变景观。最后，我 创建一种人源化的甲状腺癌异种移植小鼠模型，其中小鼠 MHCII 和 MHCI 可用于研究甲状腺癌的体内生物学并测试新疗法（包括抗甲状腺癌） Wnt 药物）针对对标准治疗耐药的甲状腺癌。在这个提案中我将测试这个假设 Wnt 信号传导导致侵袭性甲状腺癌的侵袭和转移潜力增加。瞄准 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。瞄准 2、接下来我会发现Wnt信号在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 ATC 的上调。通过完成这些研究，我将定义 Wnt 信号传导的作用，这是一个主要的信号传导 甲状腺癌中的致癌途径。我预计这些临床前研究将导致临床试验 用于治疗未分化甲状腺癌的 Wnt 抑制剂，可显着改善大多数甲状腺癌的检测和治疗 侵袭性甲状腺癌。此外，这些研究将构成强有力的研究的基础 为有前途的初级研究员制定的计划。通过这项 K08 资助和杰出导师的指导， 我将获得成为一名独立资助的成功医生所需的知识和经验- 科学家。