BLR&D Research Career Scientist Award Application

作为退伍军人事务部研究职业科学家，蒂莫西·J·霍夫曼博士的研究活动涵盖5个不同的领域 但涉及肿瘤学转译药物开发的相互关联的领域-主要是相关的 到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靶向的放射性标记受体 用于诊断、分期和治疗的治疗(诊断和治疗)药物 晚期前列腺癌(PC)。为了实现这一规划目标，我们正在评估一个 临床核医学PET中使用的Ga-68诊断正电子发射剂的组合 靶向全身给药的显影和铅-212α粒子治疗剂 BB2受体阳性前列腺癌的放射治疗。这张长凳放在床边 项目包括1)新型放射性药物的基本放射化学合成，2)体外合成 用一组具有代表性的人前列腺癌细胞系评价细胞毒性 前列腺癌从雄激素依赖到雄激素非依赖性以及 整合化疗初治和耐药细胞系，3)体内研究 这些全身注射的治疗药物可以准确地靶向受体阳性细胞。 定量PET成像在诊断和分期Ga-68标记剂中的应用 铅-212标记剂治疗人PC异种移植的疗效评价 以及5)进行必要的组织剂量测定和毒性研究，以便能够提交 医生向FDA赞助IND申请，作为翻译这些文件的最后步骤之一 药物进入临床试验。 计划活动的第二个重点涉及建立杜鲁门退伍军人管理局临床研究 通过VA绵羊IC资助生产新型短寿命PET的放射性药物(CRR) 用于临床肿瘤学和核医学研究的放射性药物。匮乏 研究放射性药学基础设施是阻碍药物翻译的主要障碍 从替补席到诊所的发现。CRR基础设施和必要的热室屏蔽 目前正在采购技术，目标是拥有完全可运行的CRR 到2019年秋季符合FDA、NRC、NHPP法规和USP指南。 计划活动的第三个重点涉及指导VA生物分子成像的操作 中心作为共享的核心研究服务运营，以提供临床前分子 利用PET、SPECT、CT、7T MRI、光学和生物发光技术提供的成像服务 退伍军人事务部的研究人员主要在肿瘤学、心脏病学和神经科学领域。 方案活动的第四和第五个重点涉及正式的科学协作和科学 临床医生和基础科学家在肿瘤学和分子成像领域的指导4 活跃的退伍军人荣誉奖，新退伍军人管理局开阔场地爆破核心奖，1名退伍军人事务部CDA2奖，1名NIH RO1奖， 和1个NCRR T32奖。

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.