VPAC1 Recpetor-Targeted PET Imaging of Prostate Cancer

VPAC1 受体靶向前列腺癌 PET 成像

• 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
• 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

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.

前列腺癌（PC）影响每六个>60岁的男性中的一个，并且在2011年将杀死超过32，000名美国男性。血清前列腺特异性抗原（PSA）测量，经直肠超声（TRUS）和磁共振成像（MRI）仍然是诊断和治疗PC的标准工具。每种方法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有关。在美国每年进行的150万次活检中，超过65%显示良性病理，表明这些标准诊断工具的假阳性率很高。这些局限性表明迫切需要非侵入性方法来a）准确地分期、定位高风险原发性PC，B）检测复发性疾病和c）以改进的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PC的早期，特异性，非侵入性放射成像。我们将靶向VPAC 1受体，它在肿瘤发生时在PC细胞上过表达。我们已经成功地将VPAC 1特异性Cu-64肽应用于前列腺癌异种移植物的成像。我们在模拟自发性人PC的TRAMP转基因小鼠中的结果说明我们的Cu-64-肽特异性且有效地靶向VPAC 1。我们还证实了Cu-64肽对模拟自发性人乳腺癌（BC）的MMTV-neu转基因小鼠中VPAC 1的特异性，包括VPAC 1的过表达。我们已经开始使用Cu-64-VPAC 1肽对人类BC进行PET成像，并获得了非常有希望的早期结果。因此，我们假设使用VPAC 1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产生最小益处的治疗或过度治疗，失禁或阳痿。我们将在四个特定目的中测试我们的假设：i）通过在无胸腺裸鼠中成像人PC异种移植物来评估对VPAC 1特异的两种Cu-64肽。ii）通过与F-18-FDG扫描、PC组织学和VPAC 1 RT-PCR和免疫组织化学比较，确定最佳Cu-64-肽在模拟人PC发病机理的TRAMP转基因小鼠中的功效，并验证TRAMP小鼠中PC恶性肿瘤的VPAC 1成像。iii）进行毒理学，获得eIND和iv）使用最适合的Cu-64-肽在25名术前PC患者中进行可行性研究。PET成像结果应与组织学结果和整个PC腺体标测结果进行统计学评价。通过靶向VPAC 1对PC进行分子PET成像的转化研究将产生经验证的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提供了一个多学科的工业团队，拥有放射性药物开发，临床试验和营销策略方面的专业知识，确保该技术从实验室到床边的成功转化。