The role of Wnt signaling in aggressive thyroid carcinoma

项目总结： 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。 超过了结直肠癌。虽然大多数患者的甲状腺癌在最初的治疗后就痊愈了，但 很大一部分患者会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，具有 糟糕的4个月存活率。虽然这些ATC通常携带常见的驱动程序突变，如BRAFV600E，但研究 这表明，大多数人也获得了Wnt途径的激活突变。此外，BRAF抑制剂有 对这些侵袭性甲状腺肿瘤的治疗效果有限。对其他癌症的研究表明，WNT 信号转导可能在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 癌症依赖于Wnt信号，尤其是低分化和侵袭性疾病。目标是 这项建议的目的是发现Wnt信号在转移性、复发性和治疗耐药甲状腺中的作用 癌症。我对BRAFV600E突变的甲状腺癌的初步数据显示Wnt/β-连环蛋白的变化 BRAF抑制后的信号转导。我的研究还创造了一种独特的甲状腺癌有机系统来研究 原发患者起源的甲状腺癌跨越了基因改变的异质性图景。最后，我 建立一种人源化的患者来源的异种甲状腺癌小鼠模型，并缺失小鼠的MHCII和 MHCI，可用于研究甲状腺癌的体内生物学和测试新的治疗方法(包括抗甲状腺激素 WNT药物)对标准治疗耐药的甲状腺癌。在这个提案中，我将检验这一假设 Wnt信号导致侵袭性甲状腺癌侵袭性和转移性增加。在AIM 1，我将确定Wnt抑制对侵袭性甲状腺癌恶性表型的体内影响。在AIM 2，我将发现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信号的驱动因素 ATC中的上调。通过这些研究的完成，我将确定WNT信号的作用，一个主要的 甲状腺癌的致癌途径。我预计这些临床前研究将导致临床试验 WNT抑制剂用于间变性甲状腺癌，极大地改善了大多数 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 一个有前途的初级调查员的项目。通过K08的资助和有成就的导师的指导， 我将获得所需的知识和经验，成为一名独立资助和成功的医生- 科学家。

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.