Mechanisms of Resistance in Sarcoma

肉瘤的耐药机制

• 批准号: 6984636
• 负责人: ERNEST U CONRAD
• 金额: $ 6万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-05-10 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6984636
• 关键词: antineoplastics; bioimaging /biomedical imaging; biopsy; cell proliferation; combination cancer therapy; combination chemotherapy; drug resistance; gene expression; gene expression profiling; human genetic material tag; human subject; human therapy evaluation; human tissue; hypoxia; image guided surgery /therapy; microarray technology; neoplasm /cancer chemotherapy; neoplasm /cancer genetics; patient oriented research; positron emission tomography; prognosis; sarcoma

Adult soft tissue sarcomas are frequently described as unusual, heterogeneous and difficult to treat malignancies. Many patients initially respond to pre-operative neo-adjuvant chemotherapy and experience better long-term survival, but response assessment is difficult, and delayed until tumor resection. Sarcoma neoadjuvant chemotherapy is based on the use of anthracyclines in combination with other active drugs such as ifosphamide and cis-platin. Our objective in this new project is to define early response patterns in pre-operative chemotherapy using PET imaging methods with specific tracers designed to assess important processes in sarcoma treatment resistance: tumor proliferation, hypoxic volume, and activity of the p-glycoprotein (P-gp) pump as factors in drug resistance. Imaging data from these studies will also be analyzed for ability to predict patient outcome. Sarcomas are notoriously hypoxic, which confers significant treatment resistance to chemo- and radiotherapy regimens. They also have variable levels of P-gp pump activity which is a mechanism that can increase drug effiux from tumor and reduce therapeutic effectiveness. We will use [11C]thymidine as a specific agent to quantitate tumor cell proliferation as a sensitive and specific measure of response prior to initiation of neoadjuvant chemotherapy, after one cycle of treatment (the first of four cycles given pre-operatively), and again prior to resection. Specifically, we will identify early changes in tumor proliferation as evidence of response. Building on our previous experience imaging sarcomas with [18F]fluoromisonidazole, we will quantitate the tumor hypoxic volume prior to treatment and correlate image derived data will tissue based laboratory assays of specific markers that relate to hypoxia, such as HIF-1alpha and VEGF expression. A new imaging agent for the P-gp pump drug efflux, [11C]verapamil, will also be used in this study. Patients will be imaged with [11C]verapamil at the same imaging times as proposed for [11C]thymidine, to quantitate levels of P-gp pump activity. Surgical samples from patient tumors in this project will be analyzed by gene microarray analysis for gene clustering patterns relevant to the processes of cell proliferation control, tissue hypoxia response, and P-gp pump activity. In this series of proposed studies, we will make critical quantitative PET derived imaging observations on specific aspects of sarcoma biology to identify early response of the tumor to treatment, mechanisms of treatment resistance, and the ability to predict patient outcome.

成人软组织肉瘤通常被描述为不常见的、异质性的和难以治疗的恶性肿瘤。许多患者最初对术前新辅助化疗有反应，并经历了更好的长期生存，但反应评估是困难的，并延迟到肿瘤切除术。肉瘤新辅助化疗是基于蒽环类药物与其他活性药物如异环磷酰胺和顺铂的联合使用。我们在这个新项目中的目标是使用PET成像方法和特定示踪剂来定义术前化疗的早期反应模式，该方法旨在评估肉瘤治疗抵抗的重要过程：肿瘤增殖、缺氧体积和p-糖蛋白的活性 （P-gp）泵作为耐药因素。这些研究的成像数据也将被 分析预测患者结局的能力。肉瘤是众所周知的缺氧，这赋予显着的治疗抵抗化疗和放疗方案。它们还具有可变水平的P-gp泵活性，这是一种可以增加肿瘤的药物流出并降低治疗效果的机制。我们将使用[11 C]胸苷作为特异性药物，在开始新辅助化疗前、一个治疗周期（术前给予的四个周期中的第一个）后和切除术前再次定量肿瘤细胞增殖，作为敏感和特异性的反应指标。具体来说，我们将确定肿瘤增殖的早期变化作为反应的证据。基于我们之前的成像经验 在使用[18 F]氟咪唑治疗肉瘤的过程中，我们将在治疗前定量肿瘤缺氧体积，并将图像来源的数据与基于组织的与缺氧相关的特异性标志物（如HIF-1 α和VEGF表达）的实验室测定相关联。本研究还将使用一种新的P-gp泵药物外排显像剂[11 C]维拉帕米。患者将在与[11 C]胸苷相同的成像时间接受[11 C]维拉帕米成像，以定量P-gp泵活性水平。本项目中的患者肿瘤手术样本将通过基因微阵列分析来分析与细胞增殖控制、组织缺氧反应和P-gp泵活性过程相关的基因聚类模式。在这一系列的 在拟议的研究中，我们将对肉瘤生物学的特定方面进行关键的定量PET衍生成像观察，以确定肿瘤对治疗的早期反应，治疗抵抗的机制以及预测患者结局的能力。