Mechanisms of Resistance in Sarcoma

肉瘤的耐药机制

• 批准号: 7236109
• 负责人: ERNEST U CONRAD
• 金额: $ 6.34万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7236109
• 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寻常的、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，并有较好的长期生存，但反应评估困难，且延迟至肿瘤切除。肉瘤新辅助化疗是基于蒽环类药物与其他活性药物如异磷酰胺和顺铂的联合使用。在这个新项目中，我们的目标是利用PET成像方法和特定的示踪剂来确定术前化疗的早期反应模式，这些示踪剂旨在评估肉瘤治疗耐药性的重要过程：肿瘤增殖、缺氧容量和p-糖蛋白的活性