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

开发。

• 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
• 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; 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

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已使人们更好地理解 癌症的病理生理学和新型信号通路的鉴定。这些途径提供了小说 “目标”（例如Akt，Mek，MTOR和受体酪氨酸激酶），导致了铅的发展 分子旨在抑制从这些途径中得出的信号传导。但是，这定位了 选择和/或验证这些靶标的巨大挑战以及铅分子的广泛分析 用于选择。分子成像技术有可能解决这些科学和 技术挑战。项目2的总体目标是制定激活或 抑制肿瘤形成以及肿瘤对疗法反应中关键途径的抑制可以 不侵入成像。由于靶向疗法通常会导致肿瘤细胞癌（GL逮捕），因此我们将瞄准 1开发并测试非侵入性报告基因增殖（从细胞进入细胞周期的S期 G1）。该记者将用于研究四种靶向治疗剂的有效性（PTK 787，A 受体酪氨酸激酶（PDGFR）抑制剂； Perifosine，Akt抑制剂； CCI 779，MTOR抑制剂和CL 1040，MEK抑制剂）。在AIM 2中，我们将使用非侵入性记者进行凋亡，以检验以下假设。 虽然靶向疗法可能不会诱导单一药物的细胞凋亡，但结合其他靶向剂 疗法或传统疗法诱导凋亡将与有效性和增强的肿瘤相关 控制。在AIM 3中，我们将开发一个用于AKT功能的记者，并使用它来测试PTK 787，Cl 779， Cl 1040和perifosine抑制Akt活性。三种分子成像方法中的每一种都将是 使用这些途径的传统“金标准”量度验证（例如，西部印迹， 免疫组织化学，激酶测定）。我们认为，项目2中提出的研究将导致 开发在测试目标治疗剂的有效性方面将是无价的工具 优化最有效组合疗法的剂量，时间表和开发。 酒吧健康：总的来说，这项研究工作将为临床试验的主动性提供理由 分子靶向疗法用于治疗恶性脑肿瘤的组合。此外， 将确定和验证成像生物标志物，用于早期评估治疗反应，这将 导致个性化患者治疗。 密歇根大学 密歇根州安阿伯 PHS 398（Rev. 09/04）第173页表格Page 2 首席调查员/计划主任（最后，第一，中间）：罗斯，布莱恩·D。 关键人员。请参阅说明。根据需要使用延续页面，以下面显示的格式提供所需的信息。 从首席研究员开始。按字母顺序列出所有其他关键人员，首先姓氏。 名称ERA CONSONS用户名组织在项目中的角色 Rehemtulla，Alnawaz Alnawaz密歇根大学项目负责人 卢克，加里。密歇根大学格鲁克大学共同投资者 其他重要的贡献者 姓名组织角色 人类胚胎干细胞kl no q是 如果所提出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的注册数： http：//stemcells.nih.qov/registrv/index.asp。 USECONTINUATIONPAGES已累及。 如果目前无法引用特定行，请包括一个说明注册表中使用的陈述。 细胞系 披露许可声明。适用于SSIR/Stronly。 Seesb1r/strinstructions。 l〜1是l〜l否 PHS 398（修订版09/04）第174页表格第2页。 编号以下页面不断 应用程序。请勿使用4A，4B等后缀。 首席调查员/计划主任（最后，第一，中间）：罗斯，布莱恩·D。 通过 初始预算期限的详细预算 直接费用仅重新示威/项目2 1 2/1/2006 11/30/2007 人事（仅申请人组织）％dollar amountrequested（省略美分） 类型努力Inst。 角色 appt。在基本工资附带 项目 名称（月）proj。薪金要求福利总计 项目负责人 Rehemtulla，Alnawaz 12 30％$ 171,922 $ 51,577 $ 15,473 $ 67,050 共同 卢克，加里研究员12 10％$ 183,500 $ 18,350 $ 5,505 $ 23,855 研究 Bhojani，Mahaveer助理12 100％$ 57,500 $ 57,500 $ 17,250 $ 74,750 研究 格里芬，劳拉（YRS 2-5）助理12 $ 37,885 研究 汉密尔顿，克里斯汀助理12 100％$ 40,896 $ 40,896 $ 12,269 $ 53,165 sbot＆hi__iot x^¿ $ 168,323 $ 50,497 $ 218,820 | 顾问费用 设备（逐项） 供应（按类别逐项列出） 细胞培养物提供$ 6,000 一次性用品$ 3,500 分子生物学试剂$ 5,000 露西林和扎拉津$ 22,000 $ 36,500 旅行 每年参加1 -2次科学会议$ 1,500 患者护理费用住院 门诊 更改和翻新（逐项计算） 其他费用（逐项字节） 动物购买$ 15,000 动物护理（SSF Inc。）$ 30,000 出版物收取$ 1,000 组织病理学$ 500 $ 46,500 财团/合同费用直接费用 初始预算PEF（项目7a，面页）的小计直接成本 $ 303,320 1 财团/合同费用设施和管理费用 初始预算期间的总直接成本 $ 303,320 1 仅SBIR/STTR：要求收费 PHS 398（修订版09/04）第175页表格4