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

开发。

基本信息

批准号：
8104197
负责人：
Alnawaz Rehemtulla
金额：
$ 39.92万
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：
2001
资助国家：
美国
起止时间：
2001-09-05 至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8104197
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 Culture Techniques Cell Cycle Cell Cycle Progression Cell Death Cell Line Cell Proliferation Cells Charge Chemical Structure Clinical Trials Combined Modality Therapy Comprehension Consensus Contrast Media Cytostatics Cytotoxic agent Data Development Differentiation Inducer Direct Costs Disclosure Dose Drug Delivery Systems E2F1 gene Equipment Fees 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 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 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 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 candidate selection caspase-3 cell killing cost cytotoxic design drug discovery efficacy testing human FRAP1 protein human embryonic stem cell in vivo inhibitor/antagonist internal control luciferin mTOR Inhibitor meetings molecular imaging neoplastic cell non-invasive monitor novel programs promoter research study response standard measure subcutaneous tool development traditional therapy treatment response tumor yeast two hybrid system

项目摘要

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信号通路的识别。 “目标”（例如 Akt、MEK、mTOR 和受体酪氨酸激酶）导致了“先导”的开发分子被设计来抑制源自这些途径的信号传导。选择和/或验证这些靶标以及广泛分析先导分子面临着巨大的挑战分子成像技术有潜力解决这些科学和问题。项目 2 的总体目标是制定策略来激活或抑制肿瘤形成以及肿瘤对治疗的反应的关键途径可以由于靶向治疗通常会导致肿瘤细胞停滞（GI 停滞），因此我们将在 Aim 中进行非侵入性成像。 1 开发并测试非侵入性增殖报告基因（细胞从细胞进入细胞周期的 S 期） G1）。该报告器将用于研究四种靶向治疗药物（PTK 787，一种）的疗效。受体酪氨酸激酶 (PDGFR) 抑制剂；Perifosine，一种 AKT 抑制剂；CCI 779，一种 mTOR 抑制剂； 1040，一种 MEK 抑制剂）。在目标 2 中，我们将使用非侵入性细胞凋亡报告基因来检验以下假设：虽然靶向治疗作为单一药物可能不会诱导细胞凋亡，但与其他靶向药物联合使用疗法或传统疗法诱导细胞凋亡将与疗效和增强的肿瘤相关在目标3中，我们将开发Akt功能的报告基因，并用它来测试PTK 787、Cl 779、 Cl 1040 和 Perifosine 均会抑制 Akt 活性。使用传统的“金标准”测量这些途径的功能（例如蛋白质印迹、免疫组织化学、激酶测定）我们相信项目 2 中提出的研究将产生以下结果：开发工具对于测试靶向治疗药物的功效以及优化其剂量、时间表并开发最有效的联合疗法。 Pub Health：总体而言，这项研究工作将为启动临床试验提供依据。此外，用于治疗恶性脑肿瘤的分子靶向疗法的组合。将识别和验证用于早期评估治疗反应的成像生物标志物，这将从而实现患者治疗的个体化。密歇根大学密歇根州安娜堡 PHS 398(Rev. 09/04) 第 173 页表格第 2 页首席研究员/项目总监（最后、第一、中间）：ROSS, Brian D. 关键人员请参阅说明，根据需要使用后续页面以如下所示的格式提供所需信息。从首席研究员开始，按字母顺序列出所有其他关键人员，姓氏在前。名称 eRA Commons 用户名项目中的组织角色 Rehemtulla, Alnawaz Alnawaz 密歇根大学项目负责人卢克，加里·格鲁克密歇根大学联合研究员其他重要贡献者名称组织在项目中的角色人类胚胎干细胞 Kl 否 Q 是如果拟议项目涉及人类胚胎干细胞，请在下面列出以下列表中特定细胞系的注册号：根据需要使用 http://stemcells.nih.qov/registrv/index.asp。如果此时无法引用特定行，请包含一项将使用注册表中的行的声明。细胞系披露许可声明仅适用于 SSIR/STTR 说明。 l~1 是 l~l 否。 PHS 398（修订版 09/04）第 174 页表格第 2 页 - 续对接下来的页码进行连续编号请勿使用 4a、4b 等后缀。首席研究员/项目总监（最后、第一、中间）：Ross, Brian D. 通过初始预算期的详细预算 FR¿中号仅直接成本 Rehemtulla/项目 2 1 2/1 /2006 11/30/2007 人员（仅限申请组织）请求金额百分比（省略分）类型努力 INST。角色 APPT 基本工资福利项目姓名（月）项目要求的薪资福利总计项目负责人雷赫姆图拉、阿尔纳瓦兹 12 30% $171,922 $51,577 $15,473 $67,050 共同 Luker, Gary 调查员 12 10% $183,500 $18,350 $5,505 $23,855 研究 Bhojani, Mahaveer 合伙人 12 100% $57,500 $57,500 $17,250 $74,750 研究劳拉·格里芬（2-5 岁）助理 12 $37,885 研究克里斯汀·汉密尔顿合伙人 12 100% $40,896 $40,896 $12,269 $53,165 SUBTOT&HI_iOt x^¿ $168,323 $50,497 $218,820 | $168,323 $50,497 $218,820 顾问费用设备（逐项列出）用品（按类别列出）细胞培养用品 $6,000 一次性用品 $3,500 分子生物学试剂 $5,000 荧光素和腔静脉黄 $22,000 $36,500 旅行每年参加 1 -2 次科学会议 $1,500 住院患者护理费用门诊病人改建和翻新（按类别逐项列出）其他费用（按类别分项）动物购买 $15,000 动物护理 (SSF inc.) $30,000 出版费 $1,000 组织病理学 $500 $46,500 财团/合同成本直接成本初始预算 PEF 直接成本小计（第 7a 项，FacePage） $303,320 1 财团/合同成本设施和管理成本初始预算期的直接成本总额 $303,320 1 仅限 SBIR/STTR：需要付费 PHS 398（修订版 09/04）第 175 页表格第 4 页