Targeting Tumor Hypoxia with Radiohalogenated Inhibitors of Carbonic Anhydrase IX

描述(由申请人提供)： 约翰·L·乔亚尔利用碳酸脱氢酶的放射性卤代抑制物进行肿瘤乏氧成像项目概述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特征和生化成分来诊断和表征疾病的机会。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。缺氧是大多数实体肿瘤的一个特征，它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，这些变化随后会影响蛋白质的表达、酶的活性、新陈代谢，甚至可能影响癌症的转移潜能。该方案的目标是开发一系列新型的碘标记分子成像药物，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，以便通过单光子发射断层扫描(SPECT)进行成像。该研究计划结合高亲和力的靶向分子来提供诊断或治疗放射性核素。在主要文献中已经描述了几类选择性和细胞膜不透膜的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被合成为非放射性标记的含碘分子，并在生化和细胞检测中验证与CA-IX的结合。显示与CA-IX高亲和力结合的化合物随后将被123I放射性标记，并在携带人类癌症异种移植瘤的小鼠中检查细胞结合、低氧依赖的肿瘤摄取和滞留。由于CA-IX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。该策略利用了对低氧诱导的CA-IX转录的严格调控；它不同于现有的低氧传感器监测氧含量或铜还原电位的机制。此外，它还将补充18FDG的肿瘤成像，而18FDG不能区分正常和缺氧。有了拟议的放射性药物，将实现个性化的患者管理，从而可以在选择适当的治疗之前评估肿瘤的缺氧情况，从而改善治疗选择和患者结果。这项工作将扩大我们之前在设计、合成和开发放射性药物方面的成功，例如用于心肌缺血成像的2-甲基-p-[123I]-碘苯基十五烷酸(BMIPP)和用于检测前列腺癌的123I标记的前列腺特异性膜抗原抑制剂。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。 公共卫生相关性： 约翰·L·乔亚尔肿瘤乏氧与碳酸脱氢酶的放射性卤化抑制剂IX项目叙述性低氧是大多数实体肿瘤的标志，已被证明与不良预后有关。这项提议的目标是开发一系列新型的低氧成像放射性药物，通过靶向低氧调节的关键酶--碳酸氢酶IX来表征患者的癌症。检测肿瘤缺氧的能力将使临床医生能够改变放射治疗的强度或寻求受肿瘤含氧量影响较小的化疗方法，并可能导致改善结果。

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.