VPAC1 Recpetor-Targeted PET Imaging of Prostate Cancer

VPAC1 受体靶向前列腺癌 PET 成像

• 批准号: 9247760
• 负责人: MATHEW laxman THAKUR
• 金额: $ 38.03万
• 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 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9247760
• 关键词: Address; Affect; African American; American; 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; Industrialization; Injectable; Investigation; Italy; Label; Laboratories; Legal patent; Life; Magnetic Resonance Imaging; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of pancreas; Malignant neoplasm of prostate; Marketing; Mediating; Methods; Modality; Molecular; Molecular Diagnosis; Monitor; Morbidity - disease rate; Mouse Mammary Tumor Virus; Multi-Institutional Clinical Trial; Mus; Neoplasm Metastasis; Nude Mice; Oncoproteins; Operative Surgical Procedures; Pathogenesis; Pathologic; Pathology; Patients; Peptides; Pharmacologic Substance; Play; Positron-Emission Tomography; Procedures; Prostate Cancer therapy; Prostate specific antigen measurement; Prostate-Specific Antigen; Quality of life; Radiopharmaceuticals; Recurrence; Recurrent Malignant Neoplasm; Recurrent disease; Reverse Transcriptase Polymerase Chain Reaction; Role; Sales; Scanning; Serum; Signal Transduction; Somatotropin; Specificity; Suggestion; Survivors; Technetium 99m; Technology; Testing; Time; Toxicology; Transgenic Mice; Translating; Translational Research; Translations; Ultrasonography; Universities; Vasoactive Intestinal Peptide; Visit; Xenograft procedure; bench to bedside; cancer imaging; clinical practice; cost; high risk; human imaging; imaging agent; improved; killings; malignant breast neoplasm; 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; tumor; 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.

描述（由申请人提供）：前列腺癌的VPAC1受体宠物成像抽象前列腺癌（PC）每六名> 60岁> 60岁的男性中有一个，并将在2011年杀死32,000多名美国男性。血清前列腺特异性抗原（PSA）测量值，直肠超声检查（TRUS）和磁共振共振（MRI Imagance（MRI）的诊断工具以及诊断工具的诊断。这些模式中的每一个都需要进行侵入性活检，以确认PC。活检与发病率和高成本有关。在美国每年进行的150万活检中，有65％以上表现出良性病理学，表明这些标准诊断工具的假阳性率很高。这些局限性表明，对a）准确阶段，局部高风险原发性PC，b）检测复发性疾病和c）具有提高可靠性的图像转移性病变的局限性了。为了解决这些问题，我们提出了PC的早期，具体，无创的放射现象。我们将靶向VPAC1受体，该受体在肿瘤发生时在PC细胞上过表达。我们已经成功地应用了VPAC1-特异性CU-64肽来对前列腺癌异种移植物进行成像。我们在流浪性转基因小鼠中模仿自发性人PC的结果表明，我们的CU-64肽特异性有效地靶向VPAC1。我们还证实了在MMTV-NEU转基因小鼠中CU-64肽对VPAC1的特异性，即模仿自发性乳腺癌（BC），包括VPAC1的过表达。我们使用CU-64-VPAC1肽在人类中启动了BC的PET成像，并具有高度有希望的早期结果。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，以及在治疗或过度治疗中，从而产生最小的益处，无能为力或无能。我们将在四个特定目的中检验我们的假设：i）通过对无胸腺裸鼠中的人类PC异种移植进行成像，评估两种针对VPAC1的CU-64肽。 ii）通过与F-18-FDG扫描，PC组织学和VPAC1 RT-PCR和免疫组织化学相比，确定模仿人PC发病机理并验证PC恶性小鼠PC恶性肿瘤的VPAC1成像的流浪性转基因小鼠的功效，并验证了PC恶性肿瘤的VPAC1成像。 iii）使用最适合的CU-64肽进行毒理学，获得EIND和IV）在25名术前PC患者中进行可行性研究。 PET成像结果应通过组织学发现和整个PC腺映射进行统计评估。通过靶向VPAC1的PC分子PET成像的这项翻译研究将产生经过PC可检测性和成像特异性验证的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，该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，可确保该技术从长凳到床边成功地翻译。