BLR&D Research Career Scientist Award Application

BLR

• 批准号: 10293558
• 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
• 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/10293558
• 关键词: Alpha Particles; Androgen Receptor; Androgens; Apoptosis; Area; Award; Bombesin; 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 Repair; Data; Dependence; Development; Diagnosis; Diagnostic; Discipline of Nuclear Medicine; Disease; Drug Kinetics; Drug usage; Endotoxins; Evaluation; Funding; Goals; Growth; Guidelines; Human; ICAM1 gene; 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; base; 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; scale up; service utilization; single photon emission computed tomography; targeted delivery; targeted treatment; theranostics; translational goal; translational research program

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，蒂莫西J.霍夫曼博士的研究活动跨越5个不同的领域， 但涉及肿瘤学转化药物开发的相关领域-主要与 分子成像和靶向放射治疗。 目前的主要研究活动集中在开发放射性标记的靶向受体 用于诊断、分期和治疗的治疗诊断（诊断和治疗）药物 晚期前列腺癌（PC）。为了实现这一方案目标，我们正在评估一个 用于临床核医学PET的Ga-68诊断性正电子发射剂的组合 用于靶向的全身递送的成像剂和Pb-212 α粒子治疗剂 蛙皮素（BB 2）受体阳性前列腺癌的放射治疗。这张长椅到床边 项目包括1）新型放射性药物的基本放射化学合成，2）体外 使用一组代表性的人前列腺癌细胞系评价细胞毒性 从雄激素依赖型到雄激素非依赖型的前列腺癌谱， 合并化疗初治细胞系和耐药细胞系，3）体内研究化疗的效用， 这些全身施用的治疗诊断剂精确地靶向受体阳性细胞， 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标记剂治疗人PC异种移植物的疗效， 和5）进行必要的组织剂量测定和毒性研究，以提交 医生向FDA申办IND申请，作为将这些申请转化为新药的最后步骤之一。 药物进入临床试验 计划活动的第二个重点是建立杜鲁门VA临床研究 放射性药物（CRR）通过VA SheEP-IC资助生产新型短寿命PET 用于临床肿瘤学和核医学研究的放射性药物。缺乏 研究放射性药物基础设施作为一个主要的障碍，防止药物转化 从实验室到诊所的新发现。CRR基础设施和必要的热室屏蔽 目前正在采购一项技术，其目标是拥有一个完全可操作的CRR， 在2019年秋季之前符合FDA、NRC、NHPP法规和USP指南。 计划活动的第三个重点是指导VA生物分子成像的操作 中心作为一个共享的核心研究服务，提供临床前分子 利用PET、SPECT、CT、7 T MRI、光学和生物发光技术的成像服务， VA研究调查人员主要在肿瘤学，心脏病学和神经科学领域。 计划活动的第四和第五个焦点涉及正式的科学合作和科学研究。 指导临床医生和基础科学家在肿瘤学和分子成像领域的4 活动VA优异奖，新的VA开放领域爆炸核心，1 VA CDA 2奖，1 NIH RO 1奖， 1个NCRR T32奖。