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.

摘要前列腺癌（PC）影响六分之一的60岁以下男性，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）仍然是诊断和治疗前列腺癌的标准工具。每一种形式都需要浸润性活检来证实PC。活组织检查与发病率和高费用有关。在美国每年进行的150万次活检中，超过65%的活检显示为良性病理，这表明这些标准诊断工具的假阳性率很高。这些局限性表明，迫切需要无创方法来a)准确分期，局部高风险原发性PC， b)检测复发性疾病，c)提高可靠性成像转移性病变。为了解决这些问题，我们建议对PC进行早期、具体、无创的放射成像。我们的目标是VPAC1受体，它在肿瘤发生时在PC细胞上过表达。我们已经成功地应用VPAC1特异性cu -64肽成像前列腺癌异种移植。我们在模拟人类自发性PC的TRAMP转基因小鼠上的实验结果表明，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mmtv - new转基因小鼠中对VPAC1的特异性，这些小鼠模拟自发性人乳腺癌（BC），包括VPAC1的过表达。我们已经开始使用Cu-64-VPAC1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VPAC1受体特异性Cu-64肽的PET成像将加速PC的诊断并有助于其管理，包括减少不必要的活检程序，减少治疗不足或过度治疗而产生的最小益处，尿失禁或阳痿。我们将在四个特定目标中验证我们的假设：i)通过在胸腺裸鼠中成像人类PC异种移植物来评估VPAC1特异性的两种Cu-64肽。ii)通过与F-18-FDG扫描、PC组织学、VPAC1 RT-PCR和免疫组织化学的比较，确定最佳cu -64肽在模拟人PC发病机制的TRAMP转基因小鼠中的疗效，验证VPAC1对TRAMP小鼠PC恶性肿瘤的显像。iii)进行毒理学，获得eIND； iv)对25例术前PC患者进行可行性研究，使用最适合的cu -64肽。PET显像结果应与组织学结果和整个PC腺体显像进行统计评估。这项针对VPAC1的PC分子PET成像的转化研究将产生一种具有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，在放射性药物开发，临床试验和营销策略方面具有专业知识，确保这项技术从实验室成功转化为临床。