MIDCAREER INVESTIGATOR AWARD

我职业生涯的最终目标是开发肿瘤代谢成像技术，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成像患者的肿瘤及其对治疗的反应。 这个建议将使我能够专注于我职业生涯中的下一个重要步骤，将这些技术纳入和测试到新化疗药物和方案的常规开发中。 我的目标是通过对伴随的代谢变化进行成像，更快地确定一种方案是否有希望，从而帮助加快新治疗方式的开发。最终，希望这将为评估新的癌症疗法带来新的范例。 作为该途径的第一步，我将继续致力于开发示踪剂，以利用PET成像DNA合成途径。 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，其抗降解并通过胸苷激酶的作用保留在细胞中。 我们在狗和人类中的初步研究表明，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检测不同肿瘤及其对治疗反应的能力。 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。 这项工作正在芭芭拉·安·卡马诺斯癌症研究所/韦恩州立大学进行，这是一个综合癌症中心，在新药发现和临床药物测试方面有着广泛的工作记录。 其中包括用于发现新药剂的PO 1赠款和用于新药第一阶段测试的UO 1赠款。 还有许多研究者发起的新药及其组合的II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。 我一直参与招聘和培养新的教师通过我的角色作为一个程序在癌症中心和血液学/肿瘤学的部门的一个部分的领导者。 这种指导作用目前正在正式确定，作为内科系正在进行的一项计划的一部分，以定期审查和协助新的教员。

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.