Targeting Tumor Microenvironment with Radiolabeled Inhibitors of Seprase (FAPalph

描述(由申请人提供)： 美国癌症协会估计，2008年美国将有140多万新的癌症病例，它将夺走50多万美国人的生命。这些病例中的绝大多数将是实体瘤，许多患者在其病程中会出现明显的转移性疾病。肿瘤细胞表面不同蛋白质的表达为通过探测肿瘤的表型特征和生化成分来诊断和表征疾病提供了机会。放射性分子选择性地与特定的肿瘤细胞表面蛋白结合，允许使用非侵入性成像技术，如分子成像或核医学，来检测肿瘤相关蛋白的存在和数量，从而提供与诊断和疾病程度、预后和治疗方案相关的重要信息。此外，由于可以制备不仅能够对疾病进行成像而且能够将治疗性放射性核素输送到疾病组织的放射性药物，因此癌症治疗可能实现。这项计划的目标是开发一系列新型的基于~(99m)Te(99mTC)的分子成像药物，靶向细胞表面蛋白Seprase(FAP1)，用于单光子发射计算机断层扫描(SPECT)。Seprase的表达通常仅限于胎儿间质组织和伤口愈合部位，但在超过90%的人类原发上皮性肿瘤(包括乳腺癌、肺癌、结直肠癌、胃癌、宫颈癌和卵巢癌)中选择性地在肿瘤相关成纤维细胞中过表达，使其成为非侵入性成像和靶向放射治疗的有吸引力的靶点。由于间质的支持和间质的参与对转移生长的启动是至关重要的，因此seprase的表达将作为一种分子标志物，基于早期发育阶段的癌症特异性生化事件来检测肿瘤的转移。该研究计划将高亲和力靶向分子与配位的螯合剂结合起来，以协调诊断或治疗放射性核素。类似的seprase抑制剂将首先被合成为非放射性标记的Re络合分子，并在生化和细胞分析中验证与seprase的结合。显示与七聚酶高亲和力结合的化合物随后将被99mTc放射性标记，并在携带人类癌症异种移植瘤的小鼠身上检查细胞结合、肿瘤摄取和滞留。由于seprase是一种细胞表面蛋白，通过直接的药代动力学分析，靶标将很容易获得。~(99m)Tc的使用将通过试剂盒的制备和SPECT扫描仪在医疗机构的普及而得到广泛应用。我们相信99mTc标记的Seprase放射性示踪剂可以用于实体瘤和转移瘤患者的诊断、分期、预后和潜在的治疗。与公共卫生相关：美国癌症协会估计，2008年美国将有140多万新的癌症病例，这些病例将夺走50多万美国人的生命，其中绝大多数将是实体肿瘤，在其病程中存在明显的转移。这项建议的目标是开发一系列针对Seprase的新型成像放射性药物，Seprase是一种蛋白，通常仅限于胎儿表达和伤口愈合部位，但在90%以上的人类原发上皮性肿瘤的癌症相关成纤维细胞中选择性过表达，使其成为非侵入性成像和靶向放射治疗的有吸引力的靶点。我们相信，该示踪剂可用于实体瘤和转移瘤患者的诊断、分期、预后和潜在的治疗。

DESCRIPTION (provided by applicant): The American Cancer Society estimates that in 2008 there will be more than 1.4 million new cases of cancer in the United States and that it will claim the lives of more than 500,000 Americans. The vast majority of these cases will be solid tumors, and overt metastatic disease will be present in many of these patients over the course of their disease. The expression of distinct proteins on the surface of tumor cells offers the opportunity to diagnose and characterize disease by probing the phenotypic identity and biochemical composition of the tumor. Radioactive molecules that selectively bind to specific tumor cell surface proteins allow the use of noninvasive imaging techniques, such as molecular imaging or nuclear medicine, for detecting the presence and quantity of tumor associated proteins, thereby providing vital information related to the diagnosis and extent of disease, prognosis and therapeutic management options. In addition, as radiopharmaceuticals can be prepared that are not only capable of imaging disease but also delivering a therapeutic radionuclide to the diseased tissue, cancer therapy may be realized. The goal of this proposal is to develop a series of novel techenium-99m (99mTc) based molecular imaging pharmaceuticals that target the cell surface protein, seprase (FAP1) for imaging by single photon emission computed tomography (SPECT). The expression of seprase is normally restricted to fetal mesenchymal tissue and sites of wound healing, but is selectively overexpressed in cancer-associated fibroblasts in greater than 90% of human primary epithelial tumors including breast, lung, colorectal, gastric, cervical and ovarian cancers, making it an attractive target to exploit for noninvasive imaging as well as targeted radiotherapy. Since stromal support, and therefore seprase involvement, is critical to the initiation of metastatic growth, seprase expression will serve as a molecular marker to detect tumor metastases based on a cancer specific biochemical event at an early stage of development. The research plan combines high affinity targeting molecules with the conjugation of a chelator for coordination of a diagnostic or therapeutic radionuclide. Analogs of seprase inhibitors will be synthesized first as non- radiolabeled rhenium complexed molecules and tested to verify binding to seprase in biochemical and cellular assays. Compounds demonstrating high affinity binding to seprase will then be radiolabeled with 99mTc and examined for cell binding, and tumor uptake and retention in mice bearing human cancer xenografts. As seprase is a cell surface protein, the target will be readily accessible, with a straightforward pharmacokinetic analysis. The use of 99mTc will lead to widespread application through kit preparation and the prevalence of SPECT scanners in medical institutions. We believe that the 99mTc labeled seprase radiotracers could be exploited for the diagnosis, staging, prognosis and potential treatment of patients with solid tumors and metastases. PUBLIC HEALTH RELEVANCE: The American Cancer Society estimates that in 2008 there will be more than 1.4 million new cases of cancer in the United States which will claim the lives of more than 500,000 Americans, and the vast majority of these cases will be solid tumors with the presence of overt metastases over the course of their disease. The goal of this proposal is to develop a series of novel imaging radiopharmaceuticals targeting seprase, a protein that is normally restricted to fetal expression and sites of wound healing, but is selectively overexpressed in cancer- associated fibroblasts of greater than 90% of human primary epithelial tumors, making it an attractive target to exploit for noninvasive imaging, as well as targeted radiotherapy. We believe that the seprase radiotracers could be exploited for the diagnosis, staging, prognosis and potential treatment of patients with solid tumors and metastases.