Wnt Signaling in the Development of Aggressive Thyroid Cancer

Wnt 信号转导在侵袭性甲状腺癌发展中的作用

• 批准号: 10385266
• 负责人: Kensey Bergdorf
• 金额: $ 0.72万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10385266
• 关键词: Adjuvant; Aggressive behavior; Antigen-Presenting Cells; BRAF gene; Behavior; Binding; CD14 gene; CRISPR interference; Cancer cell line; Cells; Co-Immunoprecipitations; Coculture Techniques; Colorectal Cancer; Combined Modality Therapy; Complex; Data; Development; Disease; Disease Progression; Drug resistance; Exhibits; Experimental Designs; FDA approved; Flow Cytometry; Goals; Histology; Human; Immune; Immunology; Immunotherapy; In Vitro; In complete remission; Incidence; Ligands; Literature; MAP Kinase Gene; MAPK Signaling Pathway Pathway; MEKs; Malignant Neoplasms; Malignant neoplasm of thyroid; Mediating; Metastatic/Recurrent; Modeling; Mus; Mutation; Organoids; Pathogenesis; Pathway interactions; Patients; Play; Property; Proteins; Recurrence; Research Design; Resistance; Role; Sampling; Signal Transduction; Survival Rate; System; Testing; Therapeutic Agents; Training; Translational Research; WNT Signaling Pathway; Work; Xenograft Model; Xenograft procedure; anaplastic thyroid cancer; beta catenin; cancer cell; cancer diagnosis; cancer type; cytokine; cytotoxicity; driver mutation; experience; immune reconstitution; immunoregulation; immunosuppressive macrophages; in vivo; inhibitor; insight; knock-down; macrophage; monocyte; mouse model; mutant; neoplastic cell; new therapeutic target; novel; peripheral blood; recruit; resistance mechanism; standard of care; success; targeted treatment; therapeutic target; therapy resistant; thyroid neoplasm; tumor; tumor behavior; tumor immunology; tumor microenvironment; tumor progression; tumor xenograft; tumor-immune system interactions

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.

项目摘要 甲状腺癌的发病率在美国正在迅速增加，预计将超过结直肠癌，成为 到2030年，癌症诊断排名第四。大多数患者对初始治疗有反应，但大约 20%会复发，10%会发展为转移性疾病。治疗选择极其有限 适用于转移性、复发性或低分化疾病的患者，如间变性甲状腺癌 (ATC)。ATC通常携带常见的驱动程序突变，如BRAFV600E，但BRAF抑制剂显示有限 在ATC治疗中的疗效。有趣的是，大多数ATC也被发现表现出 WNT活性，WNT已被证明在其他癌症类型中介导了BRAF抑制剂的耐药性。WNT也有 已被证明通过一种免疫抑制剂的发展促进了侵袭性肿瘤的行为 肿瘤微环境。我的建议的目标是确定Wnt在肿瘤进展和 间变性甲状腺癌的治疗耐药。我在开发新型椭球体方面的初步工作 而有机培养系统提供了一个独特的机会来分析Wnt抑制剂在近距离 来自原发患者样本的活体系统。在这个提案中，我将测试WNT信号的假设 在肿瘤和肿瘤微环境中驱动疾病进展和治疗抵抗的侵袭性 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 使人对BRAF抑制剂产生耐药性，并检查Wnt抑制剂在治疗高血压中的潜在用途 BRAF-抑制剂抗性和侵袭性疾病。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及WNT免疫调节特性的研究 利用人源化的小鼠肿瘤移植模型体内和体外使用单核细胞-肿瘤球体的抑制剂 共同文化，这两个都是我为这个项目开发的。在完成这些研究时，我会勾勒出 Wnt在侵袭性甲状腺癌BRAF抑制剂抵抗和免疫调节中的作用 在一种治疗选择有限的疾病中确定治疗目标。