A Multidisciplinary and Translational Approach to Hepatobiliary Malignancy

肝胆恶性肿瘤的多学科转化方法

• 批准号: 8529199
• 负责人: David R Nelson
• 金额: $ 18.69万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-15 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8529199
• 关键词: Address; Agonist; Animal Model; Apoptosis; Area; Award; BAY 54-9085; Bioinformatics; Biological Assay; Biological Markers; Blood specimen; CD4 Positive T Lymphocytes; CD8B1 gene; Cancer Center; Cancer Etiology; Cancer Model; Cancer cell line; Cell Culture Techniques; Cell Death; Cell Line; Cells; Cellular Immunity; Cessation of life; Cirrhosis; Cleaved cell; Clinical; Clinical Research; Clinical Trials; Combined Modality Therapy; Control Groups; Data; Dendritic Cells; Development; Diagnostic Neoplasm Staging; Disease; Disease Outcome; Doctor of Philosophy; Down-Regulation; Drug resistance; Early Diagnosis; Enrollment; Environment; Enzyme-Linked Immunosorbent Assay; Epidermal Growth Factor Receptor; Evolution; Excision; Faculty; Fellowship; Frequencies; Funding; Future; Gastroenterology; Gastrointestinal Neoplasms; Goals; Grant; Gray unit of radiation dose; Hepatitis C; Hepatitis C virus; Hepatobiliary; Hepatocyte; Heterogeneity; Human; IL2RA gene; Immune; Immune response; Immune system; Immunologic Markers; Immunologics; Immunosuppression; Immunosuppressive Agents; Impairment; In Vitro; Inbred BALB C Mice; Integration Host Factors; Knowledge; Ligand Binding; Liver; Liver neoplasms; Malignant - descriptor; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of liver; Mediating; Medical Students; Mentors; Modeling; Molecular; Mono-S; Mus; Mutation; Myelogenous; N.I.H. Research Support; Natural Immunity; Natural Killer Cells; Operative Surgical Procedures; Outcome; Pathway interactions; Patients; Pennsylvania; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Play; Population; Postdoctoral Fellow; Primary carcinoma of the liver cells; Process; Recruitment Activity; Recurrence; Regulatory T-Lymphocyte; Reporting; Research; Research Personnel; Research Training; Resected; Resistance; Resistance development; Role; Sampling; Serum; Signal Pathway; Signal Transduction; Source; Staging; Students; Suppressor-Effector T-Lymphocytes; T cell response; T-Cell Activation; T-Cell Proliferation; T-Lymphocyte; TNF-related apoptosis-inducing ligand; TNFRSF10A gene; TNFRSF10B gene; Testing; Therapeutic; Therapeutic Effect; Tissues; Toxic effect; Training; Training Programs; Transplantation; Treatment outcome; Tumor Burden; Tumor Immunity; Tumor-Derived; United States National Institutes of Health; Universities; Viral; base; body system; cancer cell; career; chemotherapy; clinical application; cohort; drug mechanism; effective therapy; host neoplasm interaction; improved; in vivo; insight; interdisciplinary approach; interest; kinase inhibitor; liver transplantation; mortality; mouse model; neoplastic cell; novel; novel diagnostics; novel strategies; novel therapeutics; oncology; peripheral blood; pre-clinical; programs; public health relevance; pyrosequencing; receptor; receptor expression; research study; resistance mechanism; response; therapeutic effectiveness; therapeutic target; translational approach; treatment strategy; tumor; tumor growth

DESCRIPTION (provided by applicant): In summary, HCC is the third most common cause of cancer mortality and has the fastest growing mortality rate of any cancer in the US. There are limited treatment options for this cancer and despite the advance of modern chemotherapy, the long-term outlook for patients with liver tumors remains extremely poor. Intensive research efforts have been directed toward the identification of the mechanism of initiation and progression of HCC in hopes of developing biomarkers for early diagnosis and novel treatment strategies. In order to develop rational immunological strategies for treating liver malignancies, it is important to characterize the underlying host-tumor interactions. Our preliminary data suggests that there is an ineffective immune response to HCC, which is characterized by impaired CD response, increased populations of circulating CD4+CD25+ FoxP3 regulatory T cells (Treg) and soluble CD25. We found an elevation of Tregs with enhanced suppressive function in the peripheral blood of patients with HCC which correlated with stage and tumor burden of HCC. In addition, there was an overall level of T cell suppression (based on CD4 T cell proliferation assays) and a close relationship with soluble CD25 and overall tumor burden. Soluble CD25 represents a potential simple, ELISA-based "biomarker" in the serum of T cell activation (sCD25 is cleaved from T and NK cells on activation) and because recent evidence has suggested a role in tumor related immunosuppression. In this application, we will address the hypothesis that Tregs and CD25 are increased in peripheral blood of HCC patients and promote HCC development/progression via suppression of cell mediated CD4 and CD8 T cell responses, and depletion of Tregs and/or sCD25 would enhance cellular immunity against HCC. In Specific Aim 1 we will directly evaluate the mechanisms of sCD25 induction by human HCC and modulation of immune response. In Specific Aim 1, we will also evaluate our hypothesis in patients who develop HCC and will correlate the sCD25 levels and Treg frequency / function with HCC development, progression, and response to therapy. Our proposed study will provide critical insights into the function of Tregs in liver cancer. More importantly, using a well-characterized HCC patient cohort and a well characterized animal model, we will be able to develop novel diagnostic and therapeutic strategies for HCC. In Specific Aim 2, we will characterize the expression of TRAIL and its death receptor DR4 and DR5 in human HCC tissues, determine the efficacy of TRAIL agonists on human HCC cells cultured from resected cancer tissues, and initiate clinical trials in patients with HCC using HGS-ETR. This study (initiated based on our own research data) will be the first in the world to comprehensively investigate the therapeutic potential of TRAIL agonists in human liver cancer. The outcome of our in-vitro and in-vivo studies will provide critical insights into the global effect of TRAIL agonists on human organ systems, which is essential data for broad clinical applications. PUBLIC HEALTH RELEVANCE: In conclusion, this K24 application proposes to support a unique mentoring and training program that identifies and mentors MD trainees in gastroenterology /oncology/ and hepatobiliary surgery at an early critical point in their career. I have framed a thematically related proposal that includes coursework and research opportunities for molecular and clinical research training in hepatocellular carcinoma.

描述（由申请人提供）：总而言之，HCC是癌症死亡率的第三大常见原因，并且在美国任何癌症中的死亡率最快。这种癌症的治疗选择有限，尽管现代化疗的进展，但肝肿瘤患者的长期前景仍然非常差。密集的研究工作已针对识别HCC的启动和发展机制，以期为早期诊断和新型治疗策略开发生物标志物。为了制定治疗肝脏恶性肿瘤的理性免疫学策略，表征潜在的宿主肿瘤相互作用很重要。我们的初步数据表明，对HCC的免疫反应无效，其特征是CD响应受损，循环CD4+ CD25+ FOX3调节性T细胞（Treg）和可溶性CD25的种群增加。我们发现，在HCC患者的外周血中，TREG升高具有增强的抑制功能，这与HCC的阶段和肿瘤负担相关。此外，与可溶性CD25和整体肿瘤负担相关的T细胞抑制（基于CD4 T细胞增殖测定法）和整体肿瘤负担的总体水平。可溶性CD25代表了T细胞激活血清中的潜在简单，基于ELISA的“生物标志物”（SCD25在激活时从T和NK细胞切割），并且由于最近的证据表明在肿瘤相关的免疫抑制中起作用。在此应用中，我们将解决以下假设：HCC患者的外周血中增加了Treg和CD25，并通过抑制细胞介导的CD4和CD8 T细胞反应来促进HCC的发育/进展，而Tregs和/或SCD25的耗竭将增强细胞的含量。对HCC的免疫力。在特定目标1中，我们将通过人类HCC和免疫反应的调节直接评估SCD25诱导的机制。在特定的目标1中，我们还将评估发展HCC并将SCD25水平和Treg频率 /功能与HCC发育，进展和对治疗反应相关的患者的假设。我们提出的研究将为Treg在肝癌中的功能提供关键的见解。更重要的是，使用特征良好的HCC患者队列和特征性的动物模型，我们将能够为HCC开发新颖的诊断和治疗策略。在特定目标2中，我们将表征人类HCC组织中TRAIL及其死亡受体DR4和DR5的表达，确定径向激动剂对从切除的癌症组织培养的人类HCC细胞的疗效，并使用HCS使用HCS进行HCC患者的临床试验-Etr。这项研究（基于我们自己的研究数据启动）将是世界上第一个全面研究人类肝癌中径向激动剂的治疗潜力的研究。我们的体外和体内研究的结果将提供对步道激动剂对人体器官系统的全球影响的关键见解，这是广泛临床应用的重要数据。 公共卫生相关性：总而言之，该K24的申请提议支持独特的指导和培训计划，该计划在职业生涯的早期关键点确定和指导胃肠病学 /肿瘤学 /和肝胆管手术的MD学员。我已经提出了一项主题相关的建议，其中包括肝细胞癌分子和临床研究培训的课程和研究机会。