MIDCAREER INVESTIGATOR AWARD

我职业生涯的最终目标是开发成像肿瘤新陈代谢的技术，并将从成像中获得的知识转化为癌症治疗的改进。为此，我一直专注于开发可与正电子发射断层扫描(PET)一起使用的放射性示踪剂，以成像细胞增殖。我已经将最初在我的实验室使用组织培养和小鼠开始的研究转移到对患者肿瘤及其治疗反应的成像上。这项提议将使我能够专注于我职业生涯中的下一个重要步骤，将这些技术纳入并测试新的化疗药物和方案的常规开发。我的目标是通过对伴随的代谢变化进行成像，更快地确定一种疗法是否看起来有希望，从而帮助加快新治疗模式的开发。最终，人们希望这将为评估新的癌症疗法带来一个新的范例。作为这条途径的第一步，我将继续开发示踪剂，用PET对DNA合成途径进行成像。为了使用PET进行有效的细胞增殖测量，我开发了标记的嘧啶类似物[F-18]Flt，它能抵抗降解，并通过胸苷激酶的作用保留在细胞中。我们在狗和人身上的初步研究表明，这种化合物保留在增殖组织和肿瘤中，并产生高对比度图像。我们建议进行一系列试验，以确定Flt检测不同肿瘤的能力及其对治疗的反应。我们计划将这种药物和类似的药物纳入I期和II期临床试验。这项工作是在芭芭拉·安·卡马诺斯癌症研究所/韦恩州立大学进行的，这是一个综合性癌症中心，在新药发现和临床药物测试方面有着广泛的工作记录。这包括用于发现新药的PO1赠款和用于新药第一阶段测试的UO1赠款。还有许多研究人员发起的新药及其组合的第二阶段测试方案，包括我已经启动的一些方案。我们已经开始将PET成像作为这些方案评估的一部分。这种环境对新教师的发展和指导也是极好的。我作为癌症中心一个项目的负责人和血液学/肿瘤科的一个部门的负责人，参与了新教师的招聘和培养。这一指导作用现已正式确定，作为内科系正在进行的一项计划的一部分，该计划旨在为新教师提供定期审查和援助。

The ultimate goals of my career are to develop techniques to image tumor metabolism and to translate the knowledge gained from such imaging into improvements in cancer treatment. To this end I have focused on developing radiotracers that can be used with positron emission tomography (PET) to image cell proliferation. I have moved studies, which initially began in my laboratory using tissue culture and mice, to imaging patient's tumors and their response to treatment. This proposal will allow me to concentrate on the next important step in my career, the incorporation and testing of these techniques into the routine development of new chemotherapeutics agents and regimens. My goal is to help speed the development of new treatment modalities, by more rapidly determining if a regimen looks promising by imaging the accompanying metabolic changes. Ultimately, it is hoped that this will lead to a new paradigm for the evaluation of new cancer therapies. As the first step in the pathway, I will continue to work on the development of tracers to image the DNA synthetic pathway with PET. To make valid measurements of cellular proliferation using PET, I have developed the labeled pyrimidine analog [F-18]FLT, which is resistant to degradation and retained in cells by the action of thymidine kinase. Our pilot studies in dogs and humans indicate that this compound is retained in proliferating tissues and tumors and produces high contrast images. We propose to conduct a series of trials to determine the ability of FLT to detect different tumors and their response to therapy. We plan to incorporate this and similar agents into phase I and II clinical trials. This work is being conducted at the Barbara Ann Karmanos Cancer Institute/Wayne State University, a Comprehensive Cancer Center, which has an extensive record of work on new drug discovery and clinical drug testing. This includes the presence of a PO1 grant for the discovery of new agents and a UO1 grant for phase I testing of new drugs. There are also numerous investigator initiated protocols for the phase II testing of new drugs and their combinations, including some that I have initiated. We have already begun to include PET imaging as part of the evaluation of these protocols. This environment is also excellent for the development and mentoring of new faculty. I have been involved in the recruiting and fostering of new faculty through my roles as leader of a program within the Cancer Center and a section in the Division of Hematology/Oncology. This mentoring role is now being formalized as part of an ongoing plan within the Department of Internal Medicine to provide for regular reviews of and assistance to new faculty.