Targeting Tumor Microenvironment with Radiolabeled Inhibitors of Seprase (FAPalph

使用放射性标记的 Seprase 抑制剂（FAPalph）靶向肿瘤微环境

• 批准号: 7748058
• 负责人: John Louis Joyal
• 金额: $ 18.09万
• 依托单位: MOLECULAR INSIGHT PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2010-12-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7748058
• 关键词: Acetic Acids; Active Sites; Affinity; American; American Cancer Society; Amines; Amino Acids; Autoradiography; Binding; Biochemical; Bioenergetics; Biological Assay; Breast; Cell Surface Proteins; Cells; Cellular Assay; Cervical; Chelating Agents; Colorectal; Complex; Cultured Tumor Cells; Deoxyglucose; Development; Diagnosis; Diagnostic; Dipeptidyl Peptidases; Discipline of Nuclear Medicine; Disease; Drug Kinetics; Enzyme Inhibition; Enzymes; Epithelial; Evaluation; Event; Exhibits; Fibroblasts; Glycine; Goals; Growth; HT29 Cells; Human; Image; Imaging Techniques; Immunohistochemistry; In Vitro; Infection; Inflammation; Institution; Label; Lead; Life; Lung; Malignant Neoplasms; Malignant neoplasm of ovary; Medical; Medical center; Mesenchymal; Metabolism; Metals; Modeling; Mus; Muscle; Neoplasm Metastasis; Organ; Outcome; Patient Selection; Patients; Peptide Hydrolases; Peptides; Pharmacologic Substance; Play; Preparation; Prevalence; Property; Proteins; Radiation therapy; Radioactive; Radioisotopes; Radiolabeled; Radiopharmaceuticals; Recombinants; Research; Rhenium; Role; Selection for Treatments; Series; Site; Solid Neoplasm; Species Specificity; Specificity; Staging; Stomach; Stromal Cells; Structure; Surface; Targeted Radiotherapy; Technetium 99m; Techniques; Testing; Therapeutic; Tissues; United States; Wound Healing; Xenograft procedure; analog; base; cancer therapy; cellular engineering; design; fetal; fibroblast activation protein alpha; glucose uptake; improved; in vivo; inhibitor/antagonist; metal chelator; molecular imaging; molecular marker; neoplastic cell; novel; outcome forecast; overexpression; pharmacophore; prolyl oligopeptidase; public health relevance; pyridine; radiochemical; radiotracer; selective expression; single photon emission computed tomography; tumor; tumor xenograft; uptake

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.

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，并将夺走50多万美国人的生命。这些病例中的绝大多数将是实体瘤，并且在这些患者中的许多患者在其疾病过程中将存在明显的转移性疾病。不同蛋白质在肿瘤细胞表面的表达提供了通过探测肿瘤的表型身份和生化组成来诊断和表征疾病的机会。选择性结合特定肿瘤细胞表面蛋白的放射性分子允许使用非侵入性成像技术，例如分子成像或核医学，用于检测肿瘤相关蛋白的存在和量，从而提供与疾病的诊断和程度、预后和治疗管理选项相关的重要信息。此外，由于可以制备的放射性药物不仅能够对疾病进行成像，而且还能够将治疗性放射性核素输送到患病组织，因此可以实现癌症治疗。本提案的目标是开发一系列新型锝-99m（99 mTc）为基础的分子成像药物，其靶向细胞表面蛋白Seprase（FAP 1），用于单光子发射计算机断层扫描（SPECT）成像。seprase的表达通常限于胎儿间充质组织和伤口愈合部位，但在超过90%的人原发性上皮肿瘤（包括乳腺癌、肺癌、结肠直肠癌、胃癌、宫颈癌和卵巢癌）中的癌症相关成纤维细胞中选择性过表达，使其成为开发用于非侵入性成像以及靶向放射治疗的有吸引力的靶点。由于基质支持，因此seprase参与，是转移性生长的启动至关重要的，seprase表达将作为一种分子标志物，以检测肿瘤转移的基础上，在发展的早期阶段的癌症特异性生物化学事件。该研究计划将高亲和力靶向分子与螯合剂结合，用于诊断或治疗放射性核素的协调。seprase抑制剂的类似物将首先合成为非放射性标记的非放射性复合分子，并在生物化学和细胞测定中进行测试以验证与seprase的结合。然后用99 mTc放射性标记证明与seprase具有高亲和力结合的化合物，并在携带人癌症异种移植物的小鼠中检查细胞结合以及肿瘤摄取和保留。由于seprase是一种细胞表面蛋白，因此靶标将易于接近，并具有直接的药代动力学分析。99 mTc的使用将通过试剂盒的制备和SPECT扫描仪在医疗机构中的普及而导致广泛应用。我们认为，99 mTc标记的Seprase放射性示踪剂可用于实体瘤和转移瘤患者的诊断、分期、预后和潜在治疗。公共卫生关系：美国癌症协会估计，2008年美国将有超过140万新的癌症病例，这将夺去超过50万美国人的生命，并且这些病例中的绝大多数将是实体瘤，在其疾病过程中存在明显的转移。该提案的目标是开发一系列靶向seprase的新型成像放射性药物，seprase是一种通常限于胎儿表达和伤口愈合部位的蛋白质，但在超过90%的人原发性上皮肿瘤的癌症相关成纤维细胞中选择性过表达，使其成为开发用于非侵入性成像以及靶向放射治疗的有吸引力的靶标。我们相信Seprase放射性示踪剂可用于实体瘤和转移瘤患者的诊断、分期、预后和潜在治疗。