Mechanisms of Resistance in Sarcoma

成人软组织肉瘤通常被描述为罕见的、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，但反应评估很困难，并推迟到肿瘤切除。肉瘤新辅助化疗的基础是联合使用蒽环类药物和其他活性药物，如异磷酰胺和顺铂。我们在这个新项目中的目标是使用具有特定示踪剂的PET成像方法来确定术前化疗的早期反应模式，以评估肉瘤治疗耐药的重要过程：肿瘤增殖、缺氧量和P-糖蛋白的活性。 (P-gp)泵在耐药中的作用这些研究的成像数据也将 分析预测患者结果的能力。肉瘤是出了名的低氧，对化疗和放射治疗方案有显著的抗药性。它们还具有不同水平的P-gp泵活性，这是一种可以增加肿瘤药物外流并降低疗效的机制。我们将使用[11C]胸腺嘧啶核苷作为一种特异性试剂来量化肿瘤细胞的增殖，作为在新辅助化疗开始前、治疗一个周期(术前四个周期中的第一个)以及切除前再次进行反应的灵敏和特异的测量方法。具体地说，我们将确定肿瘤增殖的早期变化作为反应的证据。以我们以前的经验为基础进行成像 使用[18F]氟异硝唑治疗肉瘤，我们将在治疗前量化肿瘤的缺氧量，并将图像导出的数据与基于组织的与缺氧相关的特定标记物的实验室分析相关联，如HIF-1α和血管内皮生长因子的表达。一种新的P-gp泵药物外排显像剂[11C]维拉帕米也将用于这项研究。患者将在与建议的[11C]胸腺嘧啶核苷成像时间相同的时间用[11C]维拉帕米进行成像，以量化P-gp泵活性水平。本项目将通过基因芯片分析来自肿瘤患者的手术样本，以寻找与细胞增殖控制、组织缺氧反应和P-gp泵活性相关的基因聚集模式。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、治疗耐药机制以及预测患者预后的能力。

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.