Devel. of Mol. Imaging Tools for Non-Invasive Monitoring of Drug Target Interact.

开发。

• 批准号: 7214533
• 负责人: Alnawaz Rehemtulla
• 金额: $ 37.29万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-12-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7214533
• 关键词: Address; Aftercare; Animals; Antibodies; Antineoplastic Agents; Apoptosis; Apoptotic; Authorization documentation; Binding; Biodistribution; Biological Assay; Biological Markers; Biological Models; Biology; Bioluminescence; Budgets; CDK4 gene; Categories; Cell Count; Cell Cycle; Cell Cycle Progression; Cell Death; Cell Line; Cell Proliferation; Cells; Charge; Chemical Structure; Clinical Trials; Combined Modality Therapy; Comprehension; Consensus; Contrast Media; Count; Cultured Cells; Cyclin-Dependent Kinases; Cytostatics; Cytotoxic agent; Data; Development; Differentiation Inducer; Direct Costs; Disclosure; Dose; Drug Delivery Systems; E2F1 gene; Equipment; Fees; Fireflies; Firefly Luciferases; Functional disorder; Future; Generations; Genetic Transcription; Genomics; Glioma; Goals; Gold; Health; Histopathology; Human Resources; Image; Imaging Device; Imaging technology; Immunohistochemistry; Implant; In Situ Nick-End Labeling; Induction of Apoptosis; Inpatients; Instruction; Interphase Cell; Invasive; Last Name; Lead; Luc Gene; Luciferases; MEKs; Malignant Neoplasms; Malignant neoplasm of brain; Measures; Mediating; Memorial Sloan-Kettering Cancer Center; Methods; Michigan; Molecular Biology; Monitor; Mus; Names; Necrosis; Numbers; Outcome; Outpatients; PDGFRB gene; Pathway interactions; Patient Care; Patients; Peptides; Perifosine; Pharmaceutical Preparations; Phase; Phosphorylated Peptide; Phosphorylation; Phosphotransferases; Play; Principal Investigator; Proliferating; Proteomics; Proto-Oncogene Proteins c-akt; Publications; Reagent; Receptor Activation; Receptor Protein-Tyrosine Kinases; Renilla; Renilla Luciferases; Reporter; Research; Research Personnel; Role; Schedule; Signal Pathway; Signal Transduction; Staining method; Stains; Standards of Weights and Measures; Surrogate Markers; System; Technology; Testing; Therapeutic Agents; Time; Transgenic Mice; Travel; Tumor Burden; Tumor Volume; Universities; Wages; Western Blotting; animal care; anti-cancer therapeutic; base; cancer therapy; caspase-3; cell killing; cost; cytotoxic; design; drug discovery; human FRAP1 protein; human embryonic stem cell; in vivo; inhibitor/antagonist; internal control; luciferin; mTOR Inhibitor; molecular imaging; neoplastic cell; non-invasive monitor; novel; programs; promoter; research study; response; subcutaneous; tool development; tumor; yeast two hybrid system

PROJECT 2: The emerging fields of genomics and proteomics have led to a better comprehension of the pathophysiology of cancer and the identification of novel signaling pathways. These pathways offer novel 'targets' (e.g. Akt, MEK, mTOR and Receptor Tyrosine Kinases) which has led to the development of 'lead molecules' designed to inhibit the signaling derived from these pathways. However, this poses a tremendous challenge for selecting and/or validating these targets and for broad profiling of lead molecules for candidate selection. Molecular imaging technologies have the potential to address these scientific and technological challenges. The overall goal of Project 2 is to develop strategies wherein activation or inhibition of key pathways in tumor formation as well as in the response of tumors to therapies can be non-invasive imaged. Since targeted therapies often lead to tumor cytostasis (Gl arrest), we will in Aim 1 develop and test a non-invasive reporter for proliferation (entry of cells to S-phase of the cell cycle from G1). This reporter will be used to investigate the efficacy of four targeted therapeutic agents (PTK 787, a receptor Tyrosine Kinase (PDGFR) inhibitor; Perifosine, an AKT inhibitor; CCI 779, an mTOR inhibitor and Cl 1040, a MEK inhibitor). In Aim 2 we will use a non-invasive reporter for apoptosis to test the hypothesis that while targeted therapies may not induce apoptosis as single agents, in combination with other targeted therapies or with traditional therapies induction of apoptosis will correlate with efficacy and enhanced tumor control. In Aim 3, we will develop a reporter for Akt function and use it to test the ability of PTK 787, Cl 779, Cl 1040 and Perifosine to inhibit Akt activity. Each of the three molecular imaging approaches will be validated using traditional "gold standard" measures of function of these pathways (e.g. Western blots, immunohistochemistry, kinase assays). We believe that studies proposed in Project 2, will result in the development of tools that will be invaluable in testing the efficacy of targeted therapeutic agents as well as in optimization of their dose, schedule and development of the most efficacious combination therapies. Pub. Health: Overall, this research effort will provide the rationale for initiation of clinical trials with combinations of molecularly targeted therapies for the treatment of malignant brain tumors. In addition, imaging biomarkers for early assessment of treatment response will be identified and validated which will lead to individualization of patient treatment. University of Michigan Ann Arbor, Michigan PHS 398(Rev. 09/04) Page 173 Form Page 2 Principal Investigator/Program Director (Last, First, Middle): ROSS, Brian D. KEY PERSONNEL. See instructions. Use continuation pages as needed to provide the required information in the format shown below. Start with Principal Investigator. List all other key personnel in alphabetical order, last name first. Name eRA Commons User Name Organization Role on Project Rehemtulla, Alnawaz Alnawaz University of Michigan Project Leader Luker, Gary. gluker University of Michigan Co-Investigator OTHER SIGNIFICANT CONTRIBUTORS Name Organization Role on Project Human Embryonic Stem Cells Kl No Q Yes If the proposed project Involves human embryonic stem cells, list below the registration number of the specific cell line(s) from thefollowing list: http://stemcells.nih.qov/registrv/index.asp. Usecontinuationpages asneeded. If a specific line cannotbe referenced at this time, include a statement that one from the Registrywill be used. Cell Line Disclosure Permission Statement. Applicable to SSIR/STTROnly. SeeSB1R/STTRinstructions. l~1 Yes l~l No PHS 398 (Rev. 09/04) Page 174 Form Page 2-continued Number the following pages consecutively throughout the application. Do not use suffixes such as 4a, 4b. Principal Investigator/Program Director (Last, first, middle): Ross, Brian D. THROUGH DETAILED BUDGET FOR INITIAL BUDGET PERIOD FR¿M DIRECT COSTS ONLY Rehemtulla/Project 2 1 2/1 /2006 11/30/2007 PERSONNEL (Applicant organization only) % DOLLAR AMOUNTREQUESTED(omit cents) TYPE EFFORT INST. ROLE ON APPT. ON BASE SALARY FRINGE PROJECT NAME (months) PROJ. SALARY REQUESTED BENEFITS TOTALS Project Leader Rehemtulla, Alnawaz 12 30% $171,922 $51,577 $15,473 $67,050 Co- Luker, Gary Investigator 12 10% $183,500 $18,350 $5,505 $23,855 Research Bhojani, Mahaveer Associate 12 100% $57,500 $57,500 $17,250 $74,750 Research Griffin, Laura (Yrs 2-5) Associate 12 $37,885 Research Hamilton, Christin Associate 12 100% $40,896 $40,896 $12,269 $53,165 SUBTOT&HI_iOt x^¿ $168,323 $50,497 $218,820 | CONSULTANT COSTS EQUIPMENT (Itemize) SUPPLIES (Itemize by category) Cell Culture Supplies $6,000 Disposable Supplies $3,500 Molecular Biology Reagents $5,000 Luciferin and Coelatrazine $22,000 $36,500 TRAVEL Attendance to 1 -2 Scientific Meetings per Year $1,500 PATIENT CARE COSTS INPATIENT OUTPATIENT ALTERATIONS AND RENOVATIONS (Itemize bycategory) OTHER EXPENSES (Itemize bycategory) Animal Purchases $15,000 Animal Care (SSF inc.) $30,000 Publication Charges $1,000 Histopathology $500 $46,500 CONSORTIUM/CONTRACTUAL COSTS DIRECT COSTS SUBTOTAL DIRECT COSTS FOR INITIAL BUDGET PEF (Item 7a, FacePage) $ 303,320 1 CONSORTIUM/CONTRACTUAL COSTS FACILITIES AND ADMINISTRATION COSTS TOTAL DIRECT COSTS FOR INITIAL BUDGET PERIOD $ 303,320 1 SBIR/STTR Only: FEE REQUESTED PHS 398 (Rev. 09/04) Page 175 Form Page 4

项目2：基因组学和蛋白质组学的新兴领域使人们更好地理解 癌症的病理生理学和新的信号通路的识别。这些路径提供了新的 “靶标”(如Akt、MEK、mTOR和受体酪氨酸激酶)导致了“铅”的发展 分子被设计用来抑制来自这些通路的信号。然而，这构成了一个 选择和/或验证这些靶标以及对铅分子进行广泛剖析的巨大挑战 进行候选人选拔。分子成像技术有可能解决这些科学和 技术挑战。项目2的总体目标是制定策略，在这些策略中激活或 抑制肿瘤形成以及肿瘤对治疗的反应中的关键途径可以 进行非侵入性成像。由于靶向治疗经常导致肿瘤细胞停滞(Gl停滞)，我们将针对 1开发和测试一种非侵入性的增殖报告(细胞进入S期-细胞周期从 G1)。这位记者将被用来调查四种靶向治疗药物(PTK 787，a 受体酪氨酸激酶(PDGFR)抑制剂；AKT抑制剂Perifosine；mTOR抑制剂CCI 779和 1040，一种MEK抑制剂)。在目标2中，我们将使用一种非侵入性的细胞凋亡报告来检验这一假设 虽然靶向治疗作为单一药物可能不会诱导细胞凋亡，但与其他靶向治疗相结合 诱导细胞凋亡的疗法或传统疗法将与疗效和增强的肿瘤相关 控制力。在目标3中，我们将开发Akt功能的报告程序，并用它来测试PTK787，Cl779， Cl1040和Perifosine对Akt活性有抑制作用。三种分子成像方法中的每一种都将 使用这些通路的功能的传统“黄金标准”测量(例如，蛋白质印迹， 免疫组织化学、酶活性测定)。我们相信，在项目2中提出的研究将导致 开发工具，这些工具将在测试靶向治疗剂的有效性以及 优化他们的剂量、计划和开发最有效的联合疗法。 酒吧。健康：总体而言，这项研究工作将为启动临床试验提供依据 分子靶向治疗恶性脑肿瘤的联合疗法。此外, 将识别和验证用于早期评估治疗反应的成像生物标记物，这将 导致患者治疗的个体化。 密歇根大学 安阿伯，密歇根州 小灵通398(09/04版)第173页表格第2页 首席研究员/项目主任(最后、第一、中间)：Ross，Brian D. 关键人员。请参阅说明。根据需要使用续页，以如下所示的格式提供所需信息。 从首席调查员开始。按字母顺序列出所有其他关键人员，姓氏在前。 名称时代共享用户名项目上的组织角色 密歇根阿尔纳瓦兹大学项目负责人Rehemtulla 卢克，这是加里。卢克是密歇根大学的联合研究员 其他重要贡献者 命名项目中的组织角色 人胚胎干细胞Kl No Q是 如果建议的项目涉及人类胚胎干细胞，请从以下列表中列出特定细胞系(S)的注册号： Http://stemcells.nih.qov/registrv/index.asp.根据需要使用二次更新页面。 如果此时不能引用特定的行，则包括一条将使用注册表中的行的声明。 细胞系 披露许可声明。适用于SSIR/STTROnly。请参阅SB1R/STR说明。L~1是L~L不是 小灵通398(09/04版)第174页表格第2页-续 从头到尾连续地给下面的页面编号 应用程序。不要使用诸如4a、4b之类的后缀。 首席研究员/项目主任(最后、第一、中间)：Ross，Brian D. 直通 初始预算期间的详细预算FR？M 仅限直接成本Rehemtulla/项目2 1 2/1/2006 11/30/2007 人员(仅限申请组织)%$AMOUNTREQUESTED(省略美分) 键入Effort Inst. 角色在 阿普特。关于基本工资和福利 工程 项目名称(月)薪资申请福利合计 项目负责人 阿尔纳瓦兹Rehemtulla 12 30%$171,922$51,577$15,473$67,050 共同-- 加里·卢克调查员12 10%$183,500$18,350$5,505$23,855 研究 博贾尼，Mahaveer助理12 100%$57,500$57,500$17,250$74,750 研究 格里芬，劳拉(2-5岁)助理12美元37,885美元 研究 哈密尔顿，克里斯汀律师事务所12 100%$40,896$40,896$12,269$53,165 子项(&I_IoT)x^？ 168,323美元50,497美元218,820美元 顾问费 设备(分项) 用品(按类别分项列出) 细胞培养提供6,000美元 一次性用品3500美元 分子生物学试剂5,000美元 荧光素和Coelatrazine$22,000 36,500美元 旅行 每年参加1-2次科学会议1,500美元 住院病人护理费用 门诊病人 改建和翻新(按类别分列) 其他费用(按类别分项列出) 购买动物：15,000美元 动物护理(SSF Inc.)3万美元 出版费1,000美元 组织病理学$500$46,500 联合体/合同成本直接成本 初步预算PEF的直接费用小计(项目7a，FacePage) 303,320美元1 财团/合同费用、设施和行政费用 初始预算期的总直接成本 303,320美元1 仅限SBIR/STTR：需要收费 小灵通398(09/04版)175页表格第4页