Wnt Signaling in the Development of Aggressive Thyroid Cancer

项目摘要 甲状腺癌的发病率在美国迅速增加，预计将超过结直肠癌， 到2030年成为第四大癌症诊断。大多数患者对初始治疗有反应，但大约 20%会复发，10%会转移。治疗选择极其有限 对于转移性、复发性或低分化疾病患者，如未分化甲状腺癌 （ATC）。ATC通常携带常见的驱动突变，如BRAFV 600 E，但BRAF抑制剂显示出有限的 治疗ATC的疗效。有趣的是，大多数ATC也被发现表现出增加 Wnt活性，并且Wnt已显示在其他癌症类型中介导BRAF抑制剂抗性。WNT还 已被证明有助于通过发展免疫抑制肿瘤的行为， 肿瘤微环境我的提案的目标是确定Wnt在肿瘤进展中的作用， 未分化甲状腺癌的治疗耐药性。我在开发新型球体方面的初步工作 和类器官培养系统提供了一个独特的机会来分析Wnt抑制剂在近中的作用， 源自原始患者样本的体内系统。在这个提议中，我将测试Wnt信号传导 在肿瘤和肿瘤微环境中， 甲状腺癌在目标1中，我将定义Wnt和MAPK信号通路之间的分子相互作用 这使得对BRAF抑制剂的耐药性，并检查Wnt抑制剂在治疗 BRAF抑制剂耐药和侵袭性疾病。在目标2中，我将阐明Wnt在发展中的作用， 免疫抑制肿瘤微环境，并研究Wnt的免疫调节特性 使用人源化肿瘤异种移植鼠模型的体内和使用单核细胞-肿瘤球体的体外抑制剂 这两种文化都是我为这个项目开发的。在完成这些研究时，我将描述 Wnt在侵袭性甲状腺癌BRAF抑制剂耐药和免疫调节中的作用 以表征具有有限治疗选择的疾病中的治疗靶点。

Project Summary The incidence of thyroid cancer is rapidly increasing in the US and is projected to surpass colorectal cancer as the 4th leading cancer diagnosis by 2030. The majority of patients respond to initial therapy, but approximately 20% will develop recurrence and 10% will develop metastatic disease. Treatment options are extremely limited for patients with metastatic, recurrent, or poorly-differentiated disease, such as anaplastic thyroid carcinoma (ATC). ATCs usually carry common driver mutations, such as BRAFV600E, but BRAF inhibitors have shown limited efficacy in the treatment of ATC. Interestingly, the majority of ATC have also been found to exhibit increased Wnt activity, and Wnt has been shown to mediate BRAF-inhibitor resistance in other cancer types. Wnt has also been shown to contribute to aggressive tumor behavior through the development of an immunosuppressive tumor microenvironment. The goal of my proposal is to define the role of Wnt in tumor progression and therapeutic resistance in anaplastic thyroid cancer. My preliminary work in the development of novel spheroid and organoid culture systems provides a unique opportunity to analyze the effects of Wnt inhibitors in a near-in vivo system derived from primary patient samples. In this proposal, I will test the hypothesis that Wnt signaling in the tumor and tumor microenvironment drive disease progression and therapeutic resistance in aggressive thyroid cancers. In Aim 1, I will define the molecular interaction between the Wnt and MAPK signaling pathways that enable resistance to BRAF inhibitors and examine the potential utility of Wnt inhibitors in the treatment of BRAF-inhibitor resistant and aggressive disease. In Aim 2, I will elucidate the role of Wnt in the development of an immunosuppressive tumor microenvironment and investigate the immunomodulatory properties of Wnt inhibitors in vivo utilizing a humanized tumor xenograft murine model and in vitro using monocyte-tumor spheroid co-cultures, both of which I have developed for this project. In completing these studies, I will delineate the contributions of Wnt in BRAF-inhibitor resistance and immunomodulation in aggressive thyroid cancer in order to characterize a therapeutic target in a disease with limited treatment options.