MIDCAREER INVESTIGATOR AWARD

我职业生涯的最终目标是开发成像肿瘤代谢的技术，并将从这种成像中获得的知识转化为癌症治疗的改进。为此，我专注于开发可与正电子发射断层扫描（PET）一起用于细胞增殖成像的放射性示踪剂。我已经开始了一些研究，最初是在我的实验室里用组织培养和老鼠，来成像病人的肿瘤和他们对治疗的反应。这项提议将使我能够专注于我职业生涯的下一个重要步骤，将这些技术纳入新的化疗药物和方案的常规开发和测试。我的目标是通过对伴随代谢变化的成像来更快地确定一种治疗方案是否有前景，从而帮助加快新治疗方式的发展。最终，希望这将导致新的癌症治疗评估的新范式。作为该途径的第一步，我将继续致力于用PET成像DNA合成途径的示踪剂的开发。为了使用PET对细胞增殖进行有效测量，我开发了标记嘧啶类似物[F-18]FLT，它耐降解并通过胸苷激酶的作用保留在细胞中。我们对狗和人类的初步研究表明，这种化合物保留在增殖组织和肿瘤中，并产生高对比度的图像。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药物纳入I期和II期临床试验。这项工作是在芭芭拉·安·卡尔玛诺斯癌症研究所/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PO1拨款用于发现新药，u01拨款用于新药的第一阶段测试。还有许多研究者发起了新药及其组合的二期试验方案，包括我发起的一些方案。我们已经开始将PET成像作为这些方案评估的一部分。这种环境也非常适合新教师的发展和指导。作为癌症中心和血液学/肿瘤学部门的一个项目的负责人，我参与了新教师的招聘和培养。这个指导角色现在正被正式确定为内科正在进行的计划的一部分，为新教员提供定期审查和帮助。

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.