Mechanisms of Resistance in Sarcoma

肉瘤的耐药机制

• 批准号: 7390731
• 负责人: ERNEST U CONRAD
• 金额: $ 9.05万
• 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/7390731
• 关键词: ABCB1 gene; Adjuvant Chemotherapy; Adriamycin PFS; Adult; Aggressive behavior; Anthracycline Antibiotics; Anthracyclines; Behavior; Biological Assay; Biological Markers; Biology; Biopsy Specimen; CDKN1A gene; Categories; Cell Proliferation; Clinical; Cluster Analysis; Data; Derivation procedure; Drug Efflux; Drug resistance; Evaluation; Excision; Gene Cluster; Gene Expression; Genes; Genomics; Goals; HIF1A gene; Histologic; Histopathologic Grade; Human; Hypoxia; Image; Imaging Device; Individual; Laboratories; Lead; Malignant Neoplasms; Measures; Mesenchymal; Methods; Microarray Analysis; Molecular; Molecular Profiling; Multi-Drug Resistance; Neoadjuvant Therapy; Neoplasm Metastasis; Operative Surgical Procedures; Outcome; P-Glycoprotein; P-Glycoproteins; Patient Care; Patients; Pattern; Pharmaceutical Preparations; Phenotype; Positron-Emission Tomography; Process; Pump; Radiation; Radiation therapy; Rate; Research; Research Personnel; Resistance; Risk; Sampling; Series; Services; Stress; System; TP53 gene; Thinking; Thymidine; Time; Tissues; Toxic effect; Tracer; Treatment Protocols; Tumor Biology; Tumor Subtype; Vascular Endothelial Growth Factors; Verapamil; base; chemotherapy; design; efflux pump; experience; improved; in vivo; middle age; molecular imaging; neoplastic cell; older patient; oncoprotein p21; outcome forecast; programs; resistance mechanism; response; sarcoma; size; soft tissue; therapeutic effectiveness; treatment planning; tumor; uptake

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.

成年软组织肉瘤通常被描述为异常，异质且难以治疗恶性肿瘤。最初，许多患者对术前的新辅助化学疗法做出反应，并经历更好的长期生存率，但是反应评估很困难，并且延迟直到肿瘤切除。肉瘤新辅助化学疗法是基于与其他活性药物（如ifosphamide和cis-platin）结合使用的蒽环类药物。我们在这个新项目中的目标是使用具有特定示踪剂的PET成像方法来定义术前化学疗法的早期反应模式，该方法旨在评估肉瘤治疗耐药性中的重要过程：肿瘤增殖，低氧体积和P-糖蛋白的活性 （p-gp）泵作为耐药性的因素。这些研究的成像数据也将是 分析了预测患者预后的能力。肉瘤是众所周知的缺氧，它赋予了对化学和放射疗法方案的明显耐药性。它们还具有可变水平的P-gp泵活性，这是一种可以提高肿瘤药物效果并降低治疗有效性的机制。我们将使用[11C]胸苷作为特定剂，以在一个治疗周期（术前给出的四个周期中的第一个）和切除之前，将肿瘤细胞增殖定量为敏感的和特定的反应量度。具体而言，我们将确定肿瘤增殖的早期变化是反应的证据。以我们以前的经验成像为基础 肉瘤具有[18F]氟甲磺胺唑唑，我们将在治疗前对肿瘤低氧体积进行定量，并将图像得出的数据相关联，将基于组织的实验室测定与缺氧有关的特定标记，例如HIF-1Alpha和VEGF表达。 P-gp泵药外排出的新成像剂[11C]维拉帕米也将在本研究中使用。患者将以[11C]维拉帕米的成像在与[11C]胸苷相同的成像时间中成像，以定量P-gp泵活性的水平。该项目中患者肿瘤的手术样本将通过基因微阵列分析分析，以分析与细胞增殖控制，组织缺氧反应和P-gp泵活性相关的基因聚类模式。在这一系列 拟议的研究，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，治疗耐药性的机制以及预测患者预后的能力。