BLR&D Research Career Scientist Award Application

BLR

基本信息

批准号：
10515298
负责人：
TIMOTHY J. HOFFMAN
金额：
--
依托单位：
HARRY S. TRUMAN MEMORIAL VA HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-10-01 至 2024-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10515298
关键词：
Alpha Particles Androgen Receptor Androgens Apoptosis Area Award Bombesin Receptor Cancer Patient Cardiology Cell Cycle Cell Line Cells Cessation of life Chemoresistance Clinical Clinical Oncology Clinical Research Clinical Trials Collaborations Cyclic GMP DNA Damage DNA Repair Data Dependence Development Diagnosis Diagnostic Discipline of Nuclear Medicine Disease Drug Kinetics Drug usage Endotoxins Evaluation Funding Goals Growth Guidelines Human In Vitro Individual Infrastructure Investigation Label Laboratories Magnetic Resonance Imaging Malignant neoplasm of prostate Maximum Tolerated Dose Measures Mentorship Methods Molecular Target National Center for Research Resources Neurosciences Oncology Optics Organ Patients Peptides Pharmaceutical Preparations Pharmacotherapy Physicians Positron Positron-Emission Tomography Preparation Procedures Production Progressive Disease Prostatic Neoplasms Pyrogens Quality Control RNA Splicing Radiation therapy Radioisotopes Radiolabeled Radiometry Radionuclide Generators Radiopharmaceuticals Radium-224 Regulation Research Research Activity Research Personnel Resistance Running Scientist Series Services Sheep Staging Sterility Targeted Radiotherapy Technology Therapeutic Therapeutic Agents Tissues Toxic effect Toxicology Translating Translations Treatment Efficacy United States United States National Institutes of Health Validation Variant Veterans Xenograft Model Xenograft procedure abiraterone advanced prostate cancer androgen sensitive antagonist bench to bedside cancer cell cancer diagnosis cancer imaging career chemotherapy cytotoxicity docetaxel dosimetry drug development drug discovery efficacy evaluation enzalutamide falls imaging biomarker imaging facilities in vivo male molecular imaging novel operation pre-clinical prevent programs prostate cancer cell line protein expression radiochemical receptor receptor expression scale up service utilization single photon emission computed tomography targeted delivery targeted treatment theranostics translational goal translational research program

Alpha Particles Androgen Receptor Androgens Apoptosis Area Award Bombesin Receptor Cancer Patient Cardiology Cell Cycle Cell Line Cells Cessation of life Chemoresistance Clinical Clinical Oncology Clinical Research Clinical Trials Collaborations Cyclic GMP DNA Damage DNA Repair Data Dependence Development Diagnosis Diagnostic Discipline of Nuclear Medicine Disease Drug Kinetics Drug usage Endotoxins Evaluation Funding Goals Growth Guidelines Human In Vitro Individual Infrastructure Investigation Label Laboratories Magnetic Resonance Imaging Malignant neoplasm of prostate Maximum Tolerated Dose Measures Mentorship Methods Molecular Target National Center for Research Resources Neurosciences Oncology Optics Organ Patients Peptides Pharmaceutical Preparations Pharmacotherapy Physicians Positron Positron-Emission Tomography Preparation Procedures Production Progressive Disease Prostatic Neoplasms Pyrogens Quality Control RNA Splicing Radiation therapy Radioisotopes Radiolabeled Radiometry Radionuclide Generators Radiopharmaceuticals Radium-224 Regulation Research Research Activity Research Personnel Resistance Running Scientist Series Services Sheep Staging Sterility Targeted Radiotherapy Technology Therapeutic Therapeutic Agents Tissues Toxic effect Toxicology Translating Translations Treatment Efficacy United States United States National Institutes of Health Validation Variant Veterans Xenograft Model Xenograft procedure abiraterone advanced prostate cancer androgen sensitive antagonist bench to bedside cancer cell cancer diagnosis cancer imaging career chemotherapy cytotoxicity docetaxel dosimetry drug development drug discovery efficacy evaluation enzalutamide falls imaging biomarker imaging facilities in vivo male molecular imaging novel operation pre-clinical prevent programs prostate cancer cell line protein expression radiochemical receptor receptor expression scale up service utilization single photon emission computed tomography targeted delivery targeted treatment theranostics translational goal translational research program

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项目摘要

As a VA Research Career Scientist, Dr. Timothy J. Hoffman’s research activities span 5 distinct but interrelated areas involving translational drug development in oncology-predominantly related to molecular imaging and targeted radiotherapy. The primary research activity is currently focused on developing radiolabeled receptor targeted theranostic (diagnostic and therapeutic) drugs for use in diagnosing, staging, and treating advanced prostate cancer (PC). To achieve this programmatic goal, we are evaluating a combination of Ga-68 diagnostic positron emitting agents for use in clinical nuclear medicine PET imaging and Pb-212 alpha particle therapeutic agents for the systemic delivery of targeted radiotherapy to Bombesin (BB2) receptor positive prostate cancers. This bench to bedside program involves 1) basic radiochemical synthesis of novel radiopharmaceuticals, 2) In vitro evaluation of cytotoxicity using a panel of human prostate cancer cell lines representative of the spectrum of prostate cancer from androgen dependent to androgen independent as well as incorporating chemotherapy naïve and resistant cell lines, 3) In vivo investigation into the utility of these systemically administered theranostic agents to accurately target receptor positive cells permitting quantitative PET imaging for diagnosis and staging of the Ga-68 labeled agent, 4) Assessing the therapeutic efficacy of the Pb-212 labeled agent for treating human PC xenografts, and 5) Performing the necessary tissue dosimetry and toxicity studies to enable the filing of a Physician sponsored IND application to the FDA as one of the final steps toward translating these agents into clinical trials. The second focus of program activity involves establishing the Truman VA Clinical Research Radiopharmacy (CRR) through VA ShEEP-IC funding for the production of novel short lived PET radiopharmaceuticals to be utilized in clinical oncology and nuclear medicine research. The lack of research radiopharmacy infrastructure as a major roadblock preventing the translation of drug discoveries from the bench to the clinic. The CRR infrastructure and necessary hot cell shielding technology is currently being procured with a goal of having a fully operational CRR that is compliant with FDA, NRC, NHPP regulations and USP guidelines by the Fall of 2019. The third focus of program activity involves directing the operation of the VA Biomolecular Imaging Center which is operated as a shared core research service to provide preclinical molecular imaging services utilizing PET, SPECT, CT, 7T MRI, Optical, and Bioluminescent technologies to VA research investigators primarily in the areas of oncology, cardiology, and neuroscience. The fourth and fifth foci of program activity involves formal scientific collaboration and scientific mentorship of clinicians and basic scientists in the areas of oncology and molecular imaging on 4 active VA Merit awards, the new VA Open Field Blast Core, 1 VA CDA2 award, 1 NIH RO1 award, and 1 NCRR T32 award.

作为VA研究职业科学家，Timothy J. Hoffman博士的研究活动跨度5不同但是相互关联的领域涉及转化药物开发在肿瘤学上相关的进行分子成像和靶向放射疗法。主要的研究活动目前专注于开发针对性的放射性标记受体疗法（诊断和治疗）药物用于诊断，分期和治疗晚期前列腺癌（PC）。为了实现这个程序化目标，我们正在评估 GA-68诊断正电子发射剂用于临床核医学PET的组合成像和PB-212α粒子治疗剂用于全身递送的靶向剂放射疗法对孟买（BB2）受体阳性前列腺取消。这个长凳到床边程序涉及1）新型放射性药物的基本放射化学合成，2）体外使用一系列人类前列腺癌细胞系评估细胞毒性从雄激素依赖到雄激素到雄激素独立的前列腺癌频谱以及结合化学疗法幼稚和抗性细胞系，3）在体内研究这些系统地施用的疗法剂，以准确靶向受体阳性细胞允许定量PET成像用于GA-68标记剂的诊断和分期，4）评估PB-212标记药物的治疗效率用于治疗人类PC Xenographictics， 5）执行必要的组织剂量法和毒性研究以实现A 医师赞助IND应用于FDA，作为翻译这些转换的最后一步临床试验的代理。计划活动的第二个重点涉及建立杜鲁门VA临床研究通过VA绵羊-IC资金用于生产新颖的Short Live Pet 可用于临床肿瘤学和核医学研究中的放射性药物。缺乏研究放射药物基础设施是一种主要障碍，阻止了药物翻译从长凳到诊所的发现。 CRR基础设施和必要的热电池屏蔽目前正在采购技术，其目标是拥有全面运行的CRR 符合FDA，NRC，NHPP法规和USP指南，到2019年秋季。程序活动的第三个焦点涉及指导VA生物分子成像的操作作为共享核心研究服务运行的中心，以提供临床前分子使用PET，SPECT，CT，7T MRI，光学和生物发光技术的成像服务 VA研究研究人员主要在肿瘤学，心脏病学和神经科学领域。计划活动的第四和第五焦点涉及正式的科学合作和科学 4 4 Active VA Merit Awards，新的VA Open Field Blast Core，1 VA CDA2奖，1 NIH RO1奖，和1个NCRR T32奖。