VPAC1 Recpetor-Targeted PET Imaging of Prostate Cancer

VPAC1 受体靶向前列腺癌 PET 成像

基本信息

批准号：
8925008
负责人：
MATHEW laxman THAKUR
金额：
$ 52.88万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-04-19 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8925008
关键词：
Address Affect African American American Atlas of Cancer Mortality in the United States Benign Biopsy Blood Tests Bronchi Cancer Histology Cancer Patient Cancerous Cell Surface Receptors Cell surface Cells Cellular Morphology Characteristics Clinic Clinical Trials Collaborations Complex Data Death Rate Development Diagnosis Diagnostic Digital Rectal Examination Disease Effectiveness Ensure European Experimental Animal Model Feasibility Studies Fingerprint Genetic Gland Healthcare Histologic Histology Human Human Resources Image Imaging Techniques Immunochemistry Immunohistochemistry Impotence Incontinence Investigation Label Laboratories Legal patent Licensing Life Magnetic Resonance Imaging Malignant - descriptor Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of pancreas Malignant neoplasm of prostate Maps Marketing Mediating Metastatic Lesion Methods Modality Molecular Molecular Diagnosis Monitor Morbidity - disease rate Mouse Mammary Tumor Virus Multi-Institutional Clinical Trial Mus Neoplasm Metastasis Nude Mice Oncogene Proteins Operative Surgical Procedures Pathogenesis Pathology Patients Peptides Pharmacologic Substance Play Positron-Emission Tomography Procedures Prostate Cancer therapy Prostate specific antigen measurement Prostate-Specific Antigen Qualifying Quality of life Radiopharmaceuticals Recurrence Recurrent Malignant Neoplasm Recurrent disease Reverse Transcriptase Polymerase Chain Reaction Role Sales Scanning Serum Signal Transduction Somatotropin Specificity Staging Suggestion Survivors Technetium 99m Technology Testing Time Toxicology Transgenic Mice Translating Translational Research Translations Ultrasonography Universities Vasoactive Intestinal Peptide Visit Xenograft procedure abstracting bench to bedside cancer imaging clinical practice cost high risk imaging agent improved killings malignant breast neoplasm meetings men multidisciplinary novel older men overexpression peptide analog pituitary adenylate cyclase activating polypeptide prostate cancer cell response screening small molecule tool transgenic adenocarcinoma of mouse prostate tumorigenesis vasoactive intestinal peptide receptor 1

项目摘要

DESCRIPTION (provided by applicant): VPAC1 Receptor-Targeted PET Imaging of Prostate Cancer Abstract Prostate cancer (PC) affects one in every six men >60 years old and will kill over 32,000 US men in 2011. Serum prostate specific antigen (PSA) measurements, transrectal ultrasonography (TRUS) and magnetic resonance imaging (MRI) remain standard tools for diagnosis and management of PC. Each of these modalities requires invasive biopsy for histologic confirmation of PC. Biopsies are associated with morbidity and high cost. More than 65% of the 1.5 million biopsies performed each year in the US show benign pathology, indicating a high false positive rate for these standard diagnostic tools. These limitations demonstrate a dire need for noninvasive methods to a) accurately stage, localized high risk primary PC, b) detect recurrent disease and c) image metastatic lesions with improved reliability. To address these issues, we propose early, specific, noninvasive radioimaging of PC. We will target VPAC1 receptors, which are overexpressed on PC cells at the onset of oncogenesis. We have successfully applied VPAC1- specific Cu-64-peptides to image prostate cancer xenografts. Our results in TRAMP transgenic mice that mimic spontaneous human PC illustrate that our Cu-64-peptides specifically and effectively target VPAC1. We have also confirmed the specificity of Cu-64 peptides for VPAC1 in MMTV-neu transgenic mice that mimic spontaneous human breast cancer (BC), including overexpression of VPAC1. We have initiated PET imaging of BC in humans using Cu-64-VPAC1 peptides with highly promising early results. Therefore, we hypothesize that PET imaging with VPAC1 receptor-specific Cu-64 peptides will expedite the diagnosis of PC and contribute to its management, including reduction in unnecessary biopsy procedures and under treatment or over treatment that yield minimal benefits, incontinence, or impotence. We will test our hypothesis in four Specific Aims: i) Evaluate two Cu-64 peptides specific for VPAC1 by imaging human PC xenografts in athymic nude mice. ii) Determine the efficacy of the best Cu-64-peptide in TRAMP transgenic mice that mimic human PC pathogenesis and validate VPAC1 imaging of PC malignancy in TRAMP mice by comparison with F-18-FDG scans, PC histology, and VPAC1 RT-PCR and immunohistochemistry. iii) Perform toxicology, obtain eIND and iv) carryout a feasibility study in 25 pre-operative PC patients, using the best suited Cu-64-peptide. PET imaging results shall be statistically evaluated with those of the histologic findings, and the entire PC gland mapping. This translational research for molecular PET imaging of PC by targeting VPAC1 will yield a PET imaging peptide validated for PC detectability and imaging specificity. Our strategic partner, NuView, offers a multidisciplinary industrial team with expertise in radiopharmaceutical development, clinical trials, and marketing strategies that ensures successful translation of this technology from bench to bedside.

描述（由申请人提供）：前列腺癌的 VPAC1 受体靶向 PET 成像摘要前列腺癌 (PC) 影响六分之一的 60 岁以上男性，2011 年将导致超过 32,000 名美国男性死亡。血清前列腺特异性抗原 (PSA) 测量、经直肠超声检查 (TRUS) 和磁共振成像 (MRI) 仍然是诊断和治疗 PC 的标准工具。这些方法中的每一种都需要侵入性活检来进行 PC 的组织学确认。活检与发病率和高成本相关。美国每年进行的 150 万例活检中，超过 65% 显示良性病理，这表明这些标准诊断工具的假阳性率很高。这些限制表明迫切需要非侵入性方法来 a) 准确分期、定位局部高风险原发性 PC，b) 检测复发性疾病，以及 c) 提高可靠性对转移性病变进行成像。为了解决这些问题，我们建议对 PC 进行早期、特异性、无创放射成像。我们将靶向 VPAC1 受体，该受体在肿瘤发生开始时在 PC 细胞上过度表达。我们已成功应用 VPAC1 特异性 Cu-64 肽对前列腺癌异种移植物进行成像。我们在模拟自发人类 PC 的 TRAMP 转基因小鼠中的结果表明，我们的 Cu-64 肽特异性且有效地靶向 VPAC1。我们还证实了 Cu-64 肽在模拟自发人类乳腺癌 (BC) 的 MMTV-neu 转基因小鼠中对 VPAC1 的特异性，包括 VPAC1 的过度表达。我们已经开始使用 Cu-64-VPAC1 肽对人类 BC 进行 PET 成像，并取得了非常有希望的早期结果。因此，我们假设使用 VPAC1 受体特异性 Cu-64 肽进行 PET 成像将加快 PC 的诊断并有助于其管理，包括减少不必要的活检程序以及减少治疗或过度治疗，从而产生最小的益处、失禁或阳痿。我们将在四个具体目标中检验我们的假设：i) 通过对无胸腺裸鼠中的人类 PC 异种移植物进行成像来评估对 VPAC1 具有特异性的两种 Cu-64 肽。 ii) 确定最佳 Cu-64 肽在模拟人类 PC 发病机制的 TRAMP 转基因小鼠中的功效，并通过与 F-18-FDG 扫描、PC 组织学和 VPAC1 RT-PCR 比较来验证 TRAMP 小鼠中 PC 恶性肿瘤的 VPAC1 成像和免疫组织化学。 iii) 进行毒理学研究，获得 eIND，并且 iv) 使用最适合的 Cu-64 肽对 25 名术前 PC 患者进行可行性研究。 PET 成像结果应与组织学结果和整个 PC 腺图谱进行统计评估。这项针对 VPAC1 的 PC 分子 PET 成像转化研究将产生一种经过验证的 PC 可检测性和成像特异性的 PET 成像肽。我们的战略合作伙伴 NuView 拥有一支多学科工业团队，他们在放射性药物开发、临床试验和营销策略方面拥有专业知识，可确保该技术从实验室成功转化为临床。