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迅速增加，预计将超越结直肠癌 到2030年，第四次领先的癌症诊断。大多数患者对初始疗法做出反应，但大约 20％将出现复发，10％将发展转移性疾病。治疗选择极为有限 对于转移性，复发性或分化不良疾病的患者，例如甲状腺癌癌 （ATC）。 ATC通常携带常见的驾驶员突变，例如BRAFV600E，但BRAF抑制剂显示有限 ATC治疗的功效。有趣的是，大多数ATC也被发现显示出来 Wnt活性和WNT已显示可介导其他癌症类型的BRAF抑制剂耐药性。 Wnt也有 被证明通过免疫抑制的发展有助于攻击性肿瘤行为 肿瘤微环境。我的提议的目的是确定Wnt在肿瘤进展中的作用 甲状腺甲状腺癌的治疗性抗性。我在新球体发展方面的初步工作 类器官培养系统提供了一个独特的机会，可以分析Wnt抑制剂在近英寸中的影响 来自主要患者样品的体内系统。在此提案中，我将测试Wnt信号传导的假设 在肿瘤和肿瘤微环境中，疾病的进展和侵略性的治疗性 甲状腺癌。在AIM 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抑制剂的抵抗力并检查了Wnt抑制剂在治疗中的潜在效用 BRAF抑制剂抗性和侵袭性疾病。在AIM 2中，我将阐明Wnt在开发中的作用 免疫抑制性肿瘤微环境并研究Wnt的免疫调节特性 利用人源化肿瘤异种移植鼠模型的体内抑制剂和使用单核细胞球体的体外抑制剂 我为这个项目开发的共同文化。在完成这些研究时，我将描述 Wnt在BRAF抑制剂耐药性和侵袭性甲状腺癌中的免疫调节作用 在具有有限治疗方案的疾病中表征治疗靶标的。