Developmental Research Program

发展研究计划

• 批准号: 7729477
• 负责人: JOSEPH G JURCIC
• 金额: $ 8.71万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7729477
• 关键词: 17-(Allylamino)-17-demethoxygeldanamycin; 90Y; Affect; Allogenic; Animals; Antibodies; Antigens; Antineoplastic Agents; Applications Grants; Area; Attenuated; Binding; Biodistribution; Biology; Biopsy; Blood specimen; Bone Marrow Purging; Bone Marrow Transplantation; Cell Culture System; Cell Line; Cell Surface Proteins; Cell surface; Cells; Chemistry; Class; Client; Clinic; Clinical; Clinical Research; Clinical Sciences; Clinical Trials; Colon Carcinoma; Complementary DNA; Cyclotrons; DHFR gene; Data; Decision Making; Development; Dihydrofolate Reductase; Discipline of Nuclear Medicine; Disease; Disease remission; Dose; Drug Delivery Systems; Drug Evaluation; Drug effect disorder; ERBB2 gene; Effectiveness; Engraftment; Enzymes; Epidermal Growth Factor Receptor; Epigenetic Process; Exposure to; Fireflies; Firefly Luciferases; Fluorescence; Folic Acid Antagonists; Foundations; Funding; Future; Gamma Cameras; Ganciclovir; Gene Amplification; Gene Expression; Gene Mutation; Gene Transfer; Genes; Genetic Enhancer Element; Glutamate Carboxypeptidase II; Goals; Grant; Growth; Hematologic Neoplasms; Human; Human Activities; Hydroxylation; Hypoxia; Image; Imaging Techniques; Imaging technology; Implant; In Vitro; Individual; Institutes; Integrin alpha6beta4; Invasive; Isotopes; J591 Monoclonal Antibody; Knowledge; Label; Laboratories; Lead; Length; Life; Link; Luciferases; Lung; Lymphoma; MS4A1 gene; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Malignant Neoplasms; Malignant neoplasm of prostate; Matrix Metalloproteinase Inhibitor; Measurable; Measurement; Measures; Medical Oncology; Memorial Sloan-Kettering Cancer Center; Metals; Methodology; Methods; Modeling; Molecular; Molecular Target; Monitor; Monoclonal Antibodies; Mus; Mutation; Myeloid Leukemia; Non-Hodgkin' s Lymphoma; Nude Rats; Numbers; Oncogenes; Organ; Organization and Administration; Oxygen; PTEN gene; Pathway interactions; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Phase I Clinical Trials; Physiological; Positron; Positron-Emission Tomography; Preparation; Production; Prostate; Proteins; Protocols documentation; Purpose; Radiation; Radiochemistry; Radioimmunotherapy; Radioisotopes; Radiolabeled; Regulation; Reporter; Reporter Genes; Reproduction spores; Research; Research Infrastructure; Research Peer Review; Research Personnel; Research Project Grants; Resolution; Retroviral Vector; Retroviridae; Sampling; Series; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Sirolimus; Spectrum Analysis; Stem cell transplant; Stem cells; Structure; Surface Antigens; Surrogate Markers; System; T-Lymphocyte; Technology; Testing; Thalidomide; Therapeutic; Therapeutic Agents; Thinking; Time; Tissues; Transcriptional Activation; Transgenic Organisms; Translating; Translations; Transplantation; Trastuzumab; Tumor Burden; Tumor Tissue; United States National Institutes of Health; Up-Regulation; Validation; Vascular Endothelial Growth Factor Receptor; Vascular Endothelial Growth Factors; Vascularization; Work; YC-1; Yttrium; antiangiogenesis therapy; base; cancer cell; cancer therapy; carbonate dehydratase; cellular transduction; clinical application; conditioning; dosimetry; fusion gene; gene therapy; high throughput screening; human FRAP1 protein; hypoxia inducible factor 1; improved; in vivo; in vivo Cellular and Molecular Imaging Centers; inhibitor/antagonist; innovative technologies; interdisciplinary approach; loss of function; molecular imaging; mouse model; multidisciplinary; neoplastic cell; neovascularization; new technology; novel; novel therapeutics; particle; pharmacokinetic model; pre-clinical; progenitor; programs; radioligand; radiotracer; receptor; research study; response; retroviral-mediated; stem; therapeutic angiogenesis; tissue culture; tool; trafficking; transgene expression; tumor; tumor xenograft; vector

E. 1. Mode of Selection of Developmental Projects For this competitive renewal of the ICMIC grant, details of decision making and oversight responsibility are included in "Organization and administration" section B. of this application. Two developmental projects will be selected and funded each year at the level of $50,000 each. The two developmental projects which have been selected are described in section E.3. below. E. 2. Progress during prior funding period 2000-2005 During the prior ICMIC grant period, we were particularly concerned about integrating molecular imaging within key programs and components of MSKCC scientific activities. A secondary goal was to select projects which had an opportunity to spin off into NIH funded research, or to integrate investigators and novel technologies into ICMIC infrastructure. In a brief summary of ongoing and completed projects, we emphasize how these goals were met for the individual projects, and to what extent these contributed to the development of additional peer-reviewed research in. molecular imaging. Developmental Project A. Imaging Dihydrofolate reductase gene amplification Project Leader: J.R.Bertino We have carried out a series of experiments to determine whether treatment of tumor bearing nude rats implanted with tumors generated from human colon cancer HCT-8 cells transduced with a retrovirus construct containing DHFR-HSVTK with antifolates will lead to an increase in gene expression. Our results suggest that in vivo treatment of these animals with TMTX results in increased gene expression of the fusion gene and this increase can be imaged using fluorescence, Gamma camera and PET scanning. Moreover, the increase in gene expression of the DHFR-HSVTK also leads to enhanced sensitivity of the tumors to ganciclovir. The results of the experiments have encouraged us to submit a grant proposal (RO1, in preparation) for therapeutic strategy for lymphoma therapy, utilizing the translational up-regulation of DHFR. Lymphoma Research Foundation, was recently obtained and will provide a bridge to NIH funding. Developmental Project B. In Vivo Imaging of Genetically Modified T Lymphocytes Project Leader: M. Sadelaine The developmental project focused on the study of a receptor specific for PSMA, a cell surface antigen over-expressed in human prostate cancer. When introduced in primary T cells by retroviral-mediated gene transfer, the Pz1 receptor redirects cytolytic activity against PSMA-positive tumor cells. The therapeutic activity of human T cells targeted to PSMA was investigated in vivo in mice bearing established tumors (1). The encouraging results form the basis for Project 2 and the clinical trial proposed therein under aim 3. Developmental Project C. Imaging Spheroid Growth and vascularization, In Vivo Project Leader: G. Sgouros , The general objectives of this proposal were to develop a model by which the seeding and vascularization of IP injected tumor into mice could be monitored by animal PET and MR imaging and, over the longer term (via an R01 mechanism), to use this model to investigate the efficacy of therapeutic agents that target tumor vasculature and/or tumor cells (e.g. alpha-emitter-labeled J591) or that inhibit neovascularization (e.g. MMP inhibitors, thalidomide). Developmental Project D. Imaging & Dosimetry of 86Y/90Y-labeled anti-GDI9 & CD20 Antibodies. Project Leader: J. Jurcic Shortly after this project was developed, problems emerged within our cyclotron and this project was deferred until Y-86 production could be guaranteed. This is one of the new projects in the ICMIC competitive renewal. Developmental Project E. Surrogate Imaging of HIF-1 a Expression Project Leader: R. Blasberg This developmental project focuses on the assessment "surrogate" marker imaging paradigms for monitoring activated hypoxia-inducible factor 1 (HIF-1) expression in tumor tissue using established radiolabeled probes that are being (or soon will be) used in clinical/patient studies. It will also include magnetic resonance imaging (MRI) and spectroscopy (MRS) which will provide additional unique information. The overall hypothesis of this proposal is that reliable assessments of HIF-1 expression can be obtained from a combination of specific PET and MRI/MRS imaging paradigms, and that it is possible to distinguish between epigenetic constitutive HIF-1 expression from physiological (hypoxia-induced) expression of HIF-1. The objective is to demonstrate a spatial and quantitative relationship (link) between the surrogate marker images and the images of HIF-1aand VEGF expression. The overall hypothesis that will be tested is that reliable assessments of HIF-1 a expression can be obtained from a combination of specific PET and MRI/MRS imaging paradigms. Developmental Project F. Imaging In vivo Trafficking and Engraftment of Transplanted Stem/Progenitor Cells Project Leader: D. Banerjee The ability to follow the trafficking of gene marked long term repopulating progenitor/stem cells by sensitive high resolution non invasive in vivo imaging techniques will have significant impact in the field of transplantation as well as cancer gene therapy. The present proposal aims to develop a sensitive noninvasive imaging method, by building on existing technologies to monitor in vivo trafficking, dynamics of engraftment as well as transgene expression of transduced long term repopulating stem/ progenitor cells following bone marrow transplantation. To determine in real time the in vivo trafficking of gene marked long term repopulating stem/progenitor cells in living mice using non invasive imaging. The aim of these studies is to determine whether the proposed approach is sensitive enough to permit in vivo imaging of stem cell/progenitor cell transplantation and engraftment. Developmental Project G. Noninvasive Quantative PET Imaging of Tumor Response with EGFR, HER2, VEGFR, PSMA and alpha6beta4 binding Radioligands (2004-2006) Project Leader: P.M. Smith-Jones This project is a multidisciplinary approach involving the nuclear medicine research lab, (Larson) and the signal transduction group (Rosen) in the program of Molecular pharmacology and chemistry within Sloan- Kettering Institute. The project involves two young investigators, Peter Smith-Jones, and David Solit, experts in radiochemistry/ medicinal chemistry and molecular targeting/medical oncology, respectively. Newly emerging cancer therapies are targeting unique cell surface proteins and receptors. The ability to rapidly assess the concentrations of these proteins on the cell surface can show the existence of metastatic disease or an indication as to the effectiveness of a particular therapy. Several targets have been identified and include Erb1 (EGFR), Erb2/neu (HER2), VEGFR, PSMA, CA IX and alpha6beta4 integrin. In current clinical trials of new anti cancer agents, there is no easy way to determine these protein levels. Current methodologies are invasive (i.e. tumor biopsies) and subjective. The purpose of this work was to develop new methods for the non invasive determination of EGFR, HER2, VEGFR, PSMA and alpha6beta4 protein levels using specific radioligands and positron emission tomography (PET). So far, this project has resulted in the development and introduction of a novel methodology for the measurement of HER2 receptor in response to the action of the drug 17- AAG. As such, this is an example of a new class of tumor response agents, Which interrogate specific molecules that are either client proteins or targeted molecules for molecular targeted therapies. In addition, we have shown that the her 2 decline is measurable and living subjects, and occurs much more rapidly than corresponding FDG changes in the same tumors. At present this information has been used to develop a patient protocol, and we anticipate that it will be possible to introduce this into clinical research within the next 12 months. In addition, for the renewal, Project 5 and four will utilize these methodologies in both in the laboratory and in patients for assessing the impact of HSP 90 inhibitor drugs, on HER2 expression. In addition laboratory based methodologies have been developed for measuring EGFR, alpha six beta for, and carbonic anhydrase nine levels in tumor xenografts in the laboratory. These methodologies as laboratory tools have been valuable in the assessment of EGFR levels, and are incorporated into project to three of the MSKCC lung spore, which is currently under review. We intend to continue this work during this work during the 2006 funded grant year. E. 3. Developmental projects planned for the first year of the competitive renewal. These development projects were chosen in part because they are multidisciplinary, and fulfill the goal of introducing new investigators or innovative technologies into the molecular imaging capabilities of ICMIC, in important areas of biology and clinical science. In addition, we believe that these developmental projects could readily provide preliminary data which could be a basis for funding under R 01 grant mechanisms. Project A provides the development of molecular imaging technology which can be correctly utilized in the clinic, as a way to provide improved dosimetry for anti-lymphoma therapy using targeted radionuclides in the form of 90Y-targeted anti-lymphoma antibodies. Project B provides novel laboratory tools for interrogating HIF-1a, a biology pathway that is highly relevant to cancer, and which relates strongly to other projects, within the current ICMIC.

E. 1。选择发展项目的方式 对于ICMIC赠款的这种竞争续约，决策和监督责任的详细信息是 包含在本申请的“组织与管理”第B节中。两个发展项目将 每年被选择和资助，每年50,000美元。这两个发展项目 已选择已在E.3节中进行了描述。以下。 E. 2.先前的资金期间2000-2005 在先前的ICMIC赠款期间，我们特别关心整合分子成像 在MSKCC科学活动的关键程序和组成部分中。第二个目标是选择 有机会跨越NIH资助的研究或整合研究人员和 新技术进入ICMIC基础设施。在正在进行和完成的项目的简短摘要中，我们 强调如何为各个项目实现这些目标，以及这些目标在多大程度上贡献了 在分子成像中开发其他同行评审研究。 发展项目A.成像二氢叶酸还原酶基因扩增 项目负责人：J.R.Bertino 我们已经进行了一系列实验，以确定是否处理裸鼠肿瘤 植入由逆转录病毒转导的人类结肠癌HCT-8细胞产生的肿瘤 含有抗染料的DHFR-HSVTK的构造将导致基因表达增加。我们的结果 表明用TMTX对这些动物进行体内治疗导致基因表达增加 融合基因和这种增加可以使用荧光，伽马相机和PET扫描来成像。 此外，DHFR-HSVTK的基因表达的增加也导致了增强的灵敏度 Ganciclovir的肿瘤。实验的结果鼓励我们提交赠款提案（RO1， 在准备中）采用淋巴瘤疗法的治疗策略，利用转化的上调 DHFR。最近获得了淋巴瘤研究基金会，并将为NIH资金提供桥梁。 发展项目B.基因修饰的T淋巴细胞的体内成像 项目负责人：M。Sadelaine 发育项目的重点是对PSMA（细胞表面抗原）特异的受体的研究 过表达人类前列腺癌。当通过逆转录病毒介导的基因引入原代T细胞时 转移，PZ1受体重定向对PSMA阳性肿瘤细胞的细胞溶解活性。治疗性 在具有既定肿瘤的小鼠中研究了靶向PSMA的人T细胞的活性（1）。 令人鼓舞的结果构成了项目2和AIM 3提出的临床试验的基础。 发展项目C.成像球体生长和血管化，体内 项目负责人：G。Sgouros， 该提案的一般目标是开发一个模型，播种和血管化 可以通过动物宠物和MR成像监测的IP注射肿瘤，从长远来看 （通过R01机制），使用该模型研究靶向肿瘤的治疗剂的功效 脉管系统和/或肿瘤细胞（例如α-发射极标记的J591）或抑制新生血管形成（例如MMP 抑制剂，沙利度胺）。 发展项目D. 86Y/90Y标记的抗GDI9和CD20抗体的成像和剂量法。 项目负责人：J。Jurcic 开发该项目后不久，我们的回旋子中出现了问题，该项目是 推迟到Y-86生产可以保证。这是ICMIC中的新项目之一 竞争性更新。 发展项目E. HIF-1 A表达的替代成像 项目负责人：R。Blasberg 这个发展项目的重点是评估“替代”标记成像范例 使用已建立 临床/患者研究中（或很快）使用的放射标记的探针。它也将包括 磁共振成像（MRI）和光谱法（MRS），将提供额外的独特 信息。该提议的总体假设是，对HIF-1表达的可靠评估可以是 从特定PET和MRI/MRS成像范式的组合获得，并且有可能 区分表观遗传组成型HIF-1表达与生理学（低氧诱导） HIF-1的表达。目的是展示在空间和定量关系（链接）之间 替代标记图像和HIF-1AAND VEGF表达的图像。总体假设是 将测试的是，对HIF-1的可靠评估可以从 特定的宠物和MRI/MRS成像范例。 发展项目F.体内贩运和移植的植入 茎/祖细胞 项目负责人：D。Banerjee 通过敏感 高分辨率非侵入性体内成像技术将对领域产生重大影响 移植以及癌症基因治疗。目前的建议旨在发展敏感的 无创成像方法，通过建立现有技术来监视体内贩运的现有技术，动力学 植入和转导的长期重现的茎/祖细胞的转基因表达 骨髓移植后。为了实时确定基因的体内运输标记很长 使用非侵入性成像的活小鼠中的茎/祖细胞的术语重盘。这些研究的目的 是确定所提出的方法是否足够敏感以允许体内成像 细胞/祖细胞移植和植入。 发育项目G.肿瘤反应的非侵入性量PET成像，EGFR， HER2，VEGFR，PSMA和Alpha6beta4结合放射线（2004-2006） 项目负责人：下午史密斯 - 琼斯 该项目是涉及核医学研究实验室（Larson）和 在斯隆 - 凯特林学院。该项目涉及两名年轻的调查员Peter Smith-Jones和David Solit， 放射化学/药物化学和分子靶向/医学肿瘤学专家。 新兴的癌症疗法靶向独特的细胞表面蛋白和受体。能力 快速评估这些蛋白质在细胞表面上的浓度可以显示转移性的存在 疾病或特定疗法有效性的指示。已经确定了几个目标 包括ERB1（EGFR），ERB2/NEU（HER2），VEGFR，PSMA，CA IX和Alpha6Beta4整合素。目前 新抗癌药的临床试验，没有简单的方法来确定这些蛋白质水平。当前的 方法论是侵入性（即肿瘤活检）和主观的。这项工作的目的是发展 EGFR，HER2，VEGFR，PSMA和Alpha6Beta4蛋白的非侵入性测定的新方法 使用特定的放射性配体和正电子发射断层扫描（PET）的水平。 到目前为止，该项目已经开发和引入了一种新颖的方法论 响应于药物17-AAG的作用的HER2受体的测量。因此，这是一个例子 一类新的肿瘤反应剂，该肿瘤反应剂询问特定的分子，这些分子要么是客户蛋白 或用于分子靶向疗法的靶向分子。此外，我们已经证明了她的2下降 是可测量的和生命的主题，并且发生的速度比相应的FDG变化要快得多 相同的肿瘤。目前，此信息已用于制定患者方案，我们预计 可以在未来12个月内将其引入临床研究中。另外，对于 续订，第5和第四个项目将在实验室和患者中使用这些方法 评估HSP 90抑制剂药物对HER2表达的影响。 此外，还开发了基于实验室的方法，用于测量EGFR，alpha Six Beta，用于 和碳酸酐酶在实验室中的肿瘤异种移植物中九个水平。这些方法为 实验室工具在评估EGFR级别中很有价值，并将其纳入项目中 目前正在审查的三个MSKCC肺孢子。 我们打算在2006年资助的赠款年期间继续这项工作。 E. 3。计划在竞争性续签的第一年计划的发展项目。 这些开发项目之所以选择部分是因为它们是多学科的，并实现了 将新的研究人员或创新技术引入ICMIC的分子成像功能， 生物学和临床科学的重要领域。此外，我们认为这些发展项目 可以很容易地提供初步数据，这可能是根据R 01赠款机制进行资金的基础。 项目A提供了可以正确利用的分子成像技术的开发 诊所，作为使用靶向放射性核素在抗淋巴瘤治疗中改进的剂量测定法 90y靶向的抗淋巴瘤抗体的形式。 B项目提供了新颖的实验室工具 询问HIF-1A，这是一种与癌症高度相关的生物学途径，并且与其他 在当前的ICMIC内。