Developmental Projects

试点项目1：每一种癌症都是从一小群异常的肿瘤细胞开始存在的。如果没有 它自身的血液供应带来氧气和营养物质，肿瘤不能生长超过1-2毫米 直径。为了超过这个范围，肿瘤会向附近的组织分泌“血管生成因子”，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，最终为肿瘤提供新的血管。这个 血管内皮细胞新生血管的诱导导致特定分子通路的激活。vbl.使用 噬菌体展示技术，Erkki Ruola hti的实验室鉴定了F3多肽 (KDEPQRRSARLSAKPAPPKPEPKPKKAPAKK)作为与内皮细胞特异结合的序列 它们是基于细胞表面核仁素的表达而形成血管的。我们最近做了 证明了该多肽序列可以以肿瘤特异性的方式靶向纳米颗粒(临床癌 决议12,6677,2007)。在目前的建议中，我们将研究F3肽作为一种工具的用途 基于PET和SPECT的肿瘤血管生成的分子成像。在具体目标1中，我们将合成一种 通过在C末端添加半胱氨酸残基来放射性标记或荧光标记F3肽以及 羟基与适当的马来酰亚胺试剂的偶联。提纯和 放射性配体的表征将通过制备反相高效液相色谱、核磁共振和质谱仪进行。 光谱分析。在特定的目标2中，我们将表征靶标的特异性和亚细胞定位 体外标记F3多肽并将其用于体内血管生成的实时成像。我们预料到 这些目标的成功完成将使实时无创和定量成像成为可能 临床前环境中的血管生成。这将为今后的临床应用奠定基础。 公共卫生：这些研究将导致开发实时成像工具，使非侵入性 癌症进展过程中新的肿瘤血管的评估。 试点项目2：骨肿瘤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，根据以下观点，对治疗的反应被认为是“不可测量的” 现有的临床反应标准(RECIST)。骨是转移性肿瘤的常见栖息地 死于前列腺癌。使用骨骼闪烁照相、普通射线照相、计算机断层照相或 磁共振成像仍然是必不可少的，使用正电子发射断层扫描或单光子成像 放射性计算机体层摄影术对骨转移的评估具有潜在的适用性。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……里面 这个临床项目，我们假设肿瘤微环境的早期变化将发生在以下几个方面 开始成功的治疗。由于肿瘤细胞内的水分子处于受限环境中 与细胞外液相比，细胞膜完整性的丧失预计会增加肿瘤的扩散。 价值观。我们最近开发了一种新的分子成像方法(功能扩散图)。 用于量化治疗引起的肿瘤内水布朗运动的变化。这一试点项目将 评价fdm作为分子成像生物标记物早期检测慢性粒细胞白血病患者治疗反应的价值 转移到骨骼的前列腺癌。10名患者将在基线的第二周接受弥散磁共振扫描 用多西紫杉醇强的松全身治疗的第9-11周。治疗和监测将按 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。所有患者都将在基线和治疗第9-11周接受标准的骨扫描。 额外的分期将在基线和指定的治疗后的临床指示下进行。 评估治疗反应的间隔时间。这项提议的最终目标是将fdm建立为一部小说。 分子成像生物标记物用于转移性骨癌治疗反应的早期评估。 公共健康：一种新的分子成像生物标记物将被评估其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 开发一种新的骨癌患者早期治疗反应的成像生物标志物。 这一生物标志物的验证将为患者护理提供个性化。

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.