Targeting Tumor Hypoxia with Radiohalogenated Inhibitors of Carbonic Anhydrase IX

使用碳酸酐酶 IX 放射性卤化抑制剂靶向肿瘤缺氧

• 批准号: 7790439
• 负责人: John Louis Joyal
• 金额: $ 11.11万
• 依托单位: MOLECULAR INSIGHT PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-22 至 2012-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7790439
• 关键词: Acetazolamide; Acids; Affinity; Alternative Therapies; Binding; Biochemical; Biological; Biological Assay; Blood Vessels; Cancer Patient; Carbonic Anhydrase Inhibitors; Cardiac; Cell Line; Cell Surface Proteins; Cell membrane; Cell surface; Cells; Cellular Assay; Cervix Neoplasms; Clinical; Competitive Binding; Complement; Copper; Detection; Development; Diagnosis; Diagnostic; Discipline of Nuclear Medicine; Disease; Drug Kinetics; Drug or chemical Tissue Distribution; EF5; Enzyme Inhibition; Enzymes; Erythrocytes; Evaluation; Exhibits; Exposure to; Foundations; Gene Expression; Genetic Transcription; Glucose Transporter; Glutamate Carboxypeptidase II; Goals; Grant; Gray unit of radiation dose; HCT116 Cells; Head and Neck Cancer; Hela Cells; Human; Hypoxia; Image; Imaging Techniques; Immunohistochemistry; In Vitro; Injection of therapeutic agent; Iodine; Ischemia; Label; Lead; Literature; Lung Adenocarcinoma; Malignant Neoplasms; Malignant neoplasm of brain; Malignant neoplasm of cervix uteri; Malignant neoplasm of prostate; Measures; Mediating; Medicine; Metabolism; Monitor; Multivariate Analysis; Mus; Neoplasm Metastasis; Non-Small-Cell Lung Carcinoma; Organ; Outcome; Oxygen; PECAM1 gene; Pathway interactions; Patient Selection; Patients; Penetration; Permeability; Pharmacologic Substance; Photons; Play; Positron-Emission Tomography; Premenopause; Preparation; Protein Isoforms; Proteins; Radiation; Radiation therapy; Radioactive; Radioactive Iodine; Radioisotopes; Radiolabeled; Radiopharmaceuticals; Regulation; Reporter; Reporting; Research; Resistance; Risk; Role; Selection for Treatments; Series; Solid Neoplasm; Solutions; Species Specificity; Specificity; Staging; Structure; Sulfonamides; Surface; Surveys; Techniques; Testing; Therapeutic; Time; TimeLine; Tin; Tissues; Transcriptional Regulation; Work; Xenograft procedure; adverse outcome; analog; base; carbonate dehydratase; chemical synthesis; chemotherapy; cobaltous chloride; design; drug efficacy; enzyme activity; extracellular; fluoromethyl 2,2-difluoro-1-(trifluoromethyl)vinyl ether; glucose uptake; improved; in vitro Assay; in vivo; inhibitor/antagonist; malignant breast neoplasm; melanoma; molecular imaging; neoplastic cell; novel; outcome forecast; prognostic; protein expression; public health relevance; radiochemical; radiotracer; research study; response; sarcoma; sensor; single photon emission computed tomography; soft tissue; success; tomography; transcription factor; tumor; uptake

DESCRIPTION (provided by applicant): John L. Joyal Imaging Tumor Hypoxia with Radiohalogenated Inhibitors of Carbonic Anhydrase IX Project Summary 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. Hypoxia is a hallmark of most solid tumors which has a direct impact on the success of radiotherapy and some chemotherapy through the reduction in tissue oxygen. It plays a vital role in triggering changes in gene expression which subsequently influence protein expression, enzymatic activities, metabolism and possibly the metastatic potential of cancer. The goal of this proposal is to develop a series of novel iodine-labeled molecular imaging pharmaceuticals that target hypoxia by binding to the hypoxia-induced cell surface protein, carbonic anhydrase IX (CA-IX) for imaging by single photon emission tomography (SPECT). The research plan combines high affinity targeting molecules to deliver a diagnostic or therapeutic radionuclide. Several classes of selective and cell membrane impermeable CA-IX inhibitors have been described in the primary literature representing a foundation for the design of radiotracers. Analogs of CA-IX inhibitors will be synthesized first as non-radiolabeled iodine-containing molecules and tested to verify binding to CA-IX in biochemical and cellular assays. Compounds demonstrating high affinity binding to CA-IX will then be radiolabeled with 123I and examined for cell binding, and hypoxia-dependent tumor uptake and retention in mice bearing human cancer xenografts. As CA-IX is a cell surface protein, the target will be readily accessible, with a straightforward pharmacokinetic analysis. The strategy takes advantage of the tight regulation of hypoxia-induced transcription of CA-IX; it is unlike the mechanism of currently available hypoxia sensors which monitor oxygen content or copper reduction potential. In addition, it will complement tumor imaging by 18FDG which cannot discriminate normoxia from hypoxia. With the proposed radiopharmaceutical, individualized patient management will be realized, whereby tumors can be assessed for hypoxia before choosing an appropriate therapy thus improving treatment selection and patient outcome. This work will expand upon our previous success in the design, synthesis and development of radiopharmaceuticals such as 2-methyl-p-[123I]-iodophenylpentadecanoic acid (BMIPP) for imaging cardiac ischemia and 123I-labeled inhibitors of prostate specific membrane antigen for the detection of prostate cancer. We believe that the 123I- labeled CA-IX radiotracers could be exploited for the diagnosis, staging, and prognosis of solid tumors. PUBLIC HEALTH RELEVANCE: John L. Joyal Imaging Tumor Hypoxia with Radiohalogenated Inhibitors of Carbonic Anhydrase IX Project Narrative Hypoxia is a hallmark of most solid tumors and has been shown to be related to poor prognosis. The goal of this proposal is to develop a series of novel hypoxia imaging radiopharmaceuticals that would allow the characterization of a patient's cancer by targeting a key hypoxia-regulated enzyme, carbonic anhydrase IX. The ability to detect tumor hypoxia would allow clinicians to alter the intensity of radiotherapy or seek chemotherapies that are less influenced by tumor oxygen content and potentially lead to improved outcomes.

描述（由申请人提供）： John L. Joyal使用碳酸酐酶IX放射性卤代抑制剂成像肿瘤缺氧项目总结肿瘤细胞表面不同蛋白质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。低氧是大多数实体瘤的标志，通过组织氧的减少直接影响放疗和某些化疗的成功。它在触发基因表达的变化中起着至关重要的作用，基因表达的变化随后影响蛋白质表达、酶活性、代谢以及可能的癌症转移潜力。本提案的目标是开发一系列新型碘标记的分子成像药物，其通过与缺氧诱导的细胞表面蛋白碳酸酐酶IX（CA-IX）结合来靶向缺氧，用于通过单光子发射断层扫描（SPECT）成像。该研究计划结合了高亲和力靶向分子，以提供诊断或治疗放射性核素。在主要文献中描述了几类选择性和细胞膜不可渗透的CA-IX抑制剂，代表了放射性示踪剂设计的基础。CA-IX抑制剂的类似物将首先合成为非放射性标记的含碘分子，并在生物化学和细胞测定中进行测试以验证与CA-IX的结合。然后用123 I放射性标记证明与CA-IX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和缺氧依赖性肿瘤摄取和保留。由于CA-IX是一种细胞表面蛋白，因此靶标将易于获得，并具有简单的药代动力学分析。该策略利用了对缺氧诱导的CA-IX转录的严格调节;它与目前可用的监测氧含量或铜还原电位的缺氧传感器的机制不同。此外，它将补充18 FDG的肿瘤成像，不能区分常氧和缺氧。使用所提出的放射性药物，将实现个体化患者管理，从而可以在选择适当的治疗之前评估肿瘤的缺氧，从而改善治疗选择和患者结局。这项工作将扩大我们以前的成功设计，合成和开发的放射性药物，如2-甲基-p-[123 I]-碘苯基十五烷酸（BMIPP）的心脏缺血成像和123 I标记的前列腺特异性膜抗原抑制剂的前列腺癌的检测。我们相信123 I标记的CA-IX放射性示踪剂可用于实体瘤的诊断、分期和预后。 公共卫生关系： John L. Joyal用碳酸酐酶IX放射性卤代抑制剂成像肿瘤缺氧叙述缺氧是大多数实体瘤的标志，已被证明与预后不良有关。该提案的目标是开发一系列新型缺氧成像放射性药物，通过靶向关键的缺氧调节酶碳酸酐酶IX来表征患者的癌症。检测肿瘤缺氧的能力将允许临床医生改变放射治疗的强度或寻求受肿瘤氧含量影响较小的化疗，并可能改善预后。