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Developmental Projects

发展项目

基本信息

批准号：
7490314
负责人：
MAHA H HUSSAIN
金额：
$ 6.72万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-04-01 至 2013-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7490314
关键词：
Angiogenesis Inhibitors Angiogenic Factor Apoptosis Binding Biochemical Markers Biological Markers Blood Circulation Blood Vessels Caliber Cancer Patient Carcinoma Caring Cell Nucleus Cell membrane Cell surface Cells Characteristics Cleaved cell Clinical Clinical Trials Consensus Cysteine Cytokeratin 18 Development Diagnosis Diagnostic radiologic examination Diffusion Diffusion Magnetic Resonance Imaging Distant Early Diagnosis Early treatment Emission-Computed Tomography Endothelial Cells Environment Epitopes Evaluation Event Foundations Funding Future Generations Goals HMGN2 Protein High Pressure Liquid Chromatography Human Image Imaging Device In Vitro Invasive Investigation Label Laboratories Lesion Ligands Magnetic Resonance Imaging Maleimides Malignant Bone Neoplasm Malignant Neoplasms Malignant neoplasm of prostate Maps Measures Metastatic Neoplasm to the Bone Metastatic Prostate Cancer Modality Molecular Monitor Motion Neoplasm Metastasis Neoplasms in Vascular Tissue Nutrient Oncogenic Organ Outcome Outcome Measure Oxygen Pathway interactions Patient Care Patients Peptides Phage Display Phase Phenotype Photons Pilot Projects Play Positron-Emission Tomography Prednisone Proliferating Prostate Protein Overexpression Proteins Public Health Radio Radiolabeled Radionuclide Imaging Reagent Research Role Scanning Serum Serum Markers Signal Transduction Site Skeletal system Specific qualifier value Specificity Staging Standards of Weights and Measures Systemic Therapy Technology Testing Therapeutic Therapeutic Intervention Time Tissues Tumor Angiogenesis Tumor-Derived Validation Vascular blood supply Water Week X-Ray Computed Tomography angiogenesis antiangiogenesis therapy base bone bone imaging cancer therapy clinical application docetaxel drug discovery extracellular fighting in vivo men millimeter molecular imaging nanoparticle neoplastic cell neovascularization novel novel strategies nucleolin peptide analog pre-clinical protein aminoacid sequence radioligand radiotracer residence response single photon emission computed tomography therapeutic angiogenesis tool tumor tumor progression water diffusion

项目摘要

PILOT PROJECT 1: Every cancer begins its existence as a tiny cluster of abnormal tumor cells. Without its own blood supply to bring in oxygen and nutrients, the tumor cannot grow larger than 1-2 millimeters in diameter. To grow beyond this, tumors secrete 'angiogenic factors' into nearby tissues, where they stimulate endothelial cells to become angiogenic. These signals cause the endothelial cells to proliferate and migrate towards the tumor, which eventually provides the tumor with new blood vessels. The induction of angiogenesis in endothelial cells results in activation of specific molecular pathways. Using phage display technology, Erkki Ruoslahti's lab identified the F3 peptide (KDEPQRRSARLSAKPAPPKPEPKPKKAPAKK) as a sequence that specifically binds to endothelial cells that are angiogenic based on the expression of nucleolin on their cell surface. We have recently demonstrated that this peptide sequence can target nanoparticles in a tumor specific manner (Clin Cancer Res. 12, 6677, 2007). In the present proposal we will investigate the utility of the F3 peptide as a tool for PET AND SPECT based molecular imaging of tumor angiogenesis. In specific aim 1 we will synthesize a radiolabeled or fluorescently labeled F3 peptide by addition of a cysteine residue at the C-terminus and conjugation of the sulfydryl group with the appropriate maleimide reagent. The purification and characterization of radioligands will be performed by preparative reverse-phase HPLC, H1 NMR and mass spectral analysis. In specific aim 2 we will characterize the target specificity and subcellular localization of labeled F3 peptide in vitro and utilize it for in vivo real time imaging of angiogenesis. We anticipate that successful completion of these aims will enable real time non-invasive and quantitative imaging of angiogenesis in a preclinical setting. This will lay the foundation for future clinical applications. Public Health: These studies will result in development of real time imaging tools that will allow non-invasive assessment of new tumor blood vessels during cancer progression. PILOT PROJECT 2: The treatment of oncogenic lesions residing in bone has advanced with an ever increasing array of therapies; however, response to treatment is considered "immeasurable" according to existing clinical response criteria (RECIST). Bone is a common site of residence of metastatic tumors derived from prostate cancer. Imaging using skeletal scintigraphy, plain radiography, computed tomography, or magnetic resonance imaging remains essential, with positron emission tomography or single-photon emission computed tomography having potential applicability for evaluating bone metastases. However, no consensus exists as to the best modality for diagnosing these lesions or for assessing treatment response. In this clinical Project, we hypothesize that early changes in tumor microenvironment will occur following initiation of successful therapy. Since water molecules within tumor cells are in a restricted environment versus extracellular water, loss of cell membrane integrity would be anticipated to increase tumor diffusion values. We have recently developed a novel molecular imaging approach (functional diffusion map (fDM)) for quantifying therapeutic-induced changes of water Brownian motion within tumors. This Pilot Project will evaluate fDM as a molecular imaging biomarker for early detection of treatment response in patients with metastatic prostate cancer to the bone. Ten patients will receive diffusion MRI scans at baseline, week 2 and week 9-11 during systemic therapy with docetaxel + prednisone. Treatment and monitoring will be per standard of care which will include physical exams and laboratory evaluations including PSA prior to each cycle of therapy. All patients will undergo a standard bone scan at baseline and at week 9-11 of therapy. Additional staging will be performed as clinically indicated at baseline and following therapy at specified intervals to assess treatment response. The ultimate goal of this proposal is to establish fDM as a novel molecular imaging biomarker for the early assessment of treatment response in metastatic bone cancer. Public Health: A novel molecular imaging biomarker will be evaluated for its ability to detect early treatment response in bone cancer patients. The ultimate outcome of this Project would provide the rationale for the development of a novel imaging biomarker for bone cancer patients to quantify early treatment response. Validation of this biomarker would provide for individualization of patient care.

试点项目 1：每种癌症都以一小群异常肿瘤细胞开始存在。没有由于自身的血液供应带来氧气和营养物质，肿瘤在生长过程中不能生长超过1-2毫米直径。为了超越这个范围，肿瘤会分泌“血管生成因子”到附近的组织中，在那里它们刺激内皮细胞生成血管。这些信号导致内皮细胞增殖并向肿瘤迁移，最终为肿瘤提供新血管。这内皮细胞中血管生成的诱导导致特定分子途径的激活。使用噬菌体展示技术，Erkki Ruoslahti 实验室鉴定出 F3 肽 (KDEPQRRSARLSAKPAPPKPEPKPKKAPAKK) 作为与内皮细胞特异性结合的序列基于细胞表面核仁素的表达而产生血管生成。我们最近有证明该肽序列可以以肿瘤特异性方式靶向纳米颗粒（Clin Cancer 资源。 12, 6677, 2007）。在本提案中，我们将研究 F3 肽作为工具的效用基于 PET 和 SPECT 的肿瘤血管生成分子成像。在具体目标 1 中，我们将综合通过在 C 末端添加半胱氨酸残基进行放射性标记或荧光标记的 F3 肽，以及巯基与适当的马来酰亚胺试剂的缀合。纯化和放射性配体的表征将通过制备型反相 HPLC、H1 NMR 和质谱进行光谱分析。在具体目标 2 中，我们将描述目标特异性和亚细胞定位体外标记的 F3 肽并将其用于血管生成的体内实时成像。我们预计成功完成这些目标将能够实现实时无创定量成像临床前环境中的血管生成。这将为未来的临床应用奠定基础。公共卫生：这些研究将导致实时成像工具的开发，该工具将允许非侵入性评估癌症进展过程中的新肿瘤血管。试点项目 2：骨内致癌病变的治疗取得了前所未有的进展越来越多的治疗方法；然而，根据研究，对治疗的反应被认为是“不可估量的” 现有的临床反应标准（RECIST）。骨是转移性肿瘤的常见驻留部位来自前列腺癌。使用骨骼闪烁扫描、普通放射线照相、计算机断层扫描或磁共振成像仍然至关重要，包括正电子发射断层扫描或单光子发射计算机断层扫描对于评估骨转移具有潜在的适用性。然而，没有对于诊断这些病变或评估治疗反应的最佳方式存在共识。在在这个临床项目中，我们假设肿瘤微环境的早期变化将发生在成功治疗的开始。由于肿瘤细胞内的水分子处于有限的环境中与细胞外水相比，细胞膜完整性的丧失预计会增加肿瘤扩散价值观。我们最近开发了一种新颖的分子成像方法（功能扩散图（fDM））用于量化治疗引起的肿瘤内水布朗运动的变化。该试点项目将评估 fDM 作为分子成像生物标志物，用于早期检测患有以下疾病的患者的治疗反应前列腺癌骨转移。 10 名患者将在第 2 周基线时接受扩散 MRI 扫描以及多西紫杉醇 + 泼尼松全身治疗期间的第 9-11 周。治疗和监测将按照护理标准，包括体检和实验室评估，包括每次检查前的 PSA 治疗周期。所有患者将在基线和治疗第 9-11 周接受标准骨扫描。将根据基线和指定治疗后的临床指示进行额外的分期评估治疗反应的时间间隔。该提案的最终目标是将 fDM 建立为一种新颖的用于早期评估转移性骨癌治疗反应的分子成像生物标志物。公共卫生：将评估一种新型分子成像生物标志物检测早期治疗的能力骨癌患者的反应。该项目的最终结果将为为骨癌患者开发一种新型成像生物标志物，以量化早期治疗反应。该生物标志物的验证将为患者护理提供个性化服务。