Design and Evaluation of Hypoxia Enhanced Bombesin Analogs for Prostate Cancer

职位描述(申请人提供)：职业目标：我目前的目标是获得所需的培训，成为一名能够为临床试验开发诊断/治疗癌症药物的翻译研究人员。我的长期目标是成为一名专门从事癌症研究的学术医学中心的独立研究科学家。 研究项目：我们的建议是通过将低氧捕捉剂引入肿瘤特异性靶向肽的结构中来提高诊断放射性药物检测前列腺癌的有效性。我们建议通过将硝基咪唑(缺氧捕捉剂)加入到蛙素(BBN)多肽的结构中来检验我们的理论。建议的1111n-BBN类似物有望显示诊断试剂在前列腺癌中的滞留时间增加。肿瘤缺氧区滞留时间的增加将通过产生更高的肿瘤与非靶点比率来提供显著增强的诊断图像。如果成功，这项技术可以极大地提高BBN和其他肿瘤特异性靶向小分子、多肽和抗体的疗效。 职业发展：本申请中的导师团队旨在教育申请者成为一名转化型癌症研究人员所需的技能。基础和临床前实验室培训将由导师(霍夫曼)和共同导师(沃尔克特)提供。联合导师(佩里)将为申请者提供放射性药物开发的临床视角及其与患者护理的关系。正式的培训计划将包括授课讲座、出席研讨会报告、使用老鼠模型和肿瘤学的实践培训，以及使用分子和解剖成像技术的实践培训。 环境：申请人可以进入霍夫曼博士的实验室(2600平方英尺)。为拟议的低氧增强蛙素类似物的合成和评估提供了充分的准备。此外，申请者还将获得退伍军人管理局动物研究设施、生物分子成像中心、退伍军人管理局核医学服务、MU细胞和免疫生物学核心设施以及MU结构生物学核心。 相关性：目前在美国，前列腺癌是男性癌症相关死亡的第二大原因。我们将开发和评估的诊断放射性药物将为临床医生提供前列腺癌检测和分期的关键工具。这项提案中开发的技术可能会显著提高诊断和治疗药物对前列腺癌和其他形式癌症的疗效。

DESCRIPTION (provided by applicant): Career Goals: My immediate goals are to obtain the required training to become a translational research capable of developing diagnostic/therapeutic cancer agents for clinical trials. My long-term goals are to becoming an independent research scientist at an academic medical center specializing in cancer research. Research Project: Our proposal is to enhance the efficacy of diagnostic radiopharmaceuticals for the detection of prostate cancer by incorporating hypoxia trapping agents into the structure of tumor specific targeted peptides. We propose to test our theory by incorporating nitroimidazoles (hypoxia trapping agents) into the structure of the Bombesin (BBN) peptide. The proposed 1111n-BBN analogs are expected to exhibit increased residence time of the diagnostic agent in prostate tumors. The increase in retention time in the hypoxic sections of the tumor will provide significantly enhanced diagnostic images by yielding higher tumor to non-target ratios. If successful, this technology could drastically enhance the efficacy of BBN and other tumor specific targeted small molecules, peptides and antibodies. Career Development: The mentorship team in this application is designed to educate the applicant in the necessary skill set to become a translational cancer researcher. The basic and preclinical laboratory training will be provided by the mentor (Hoffman) and co-mentor (Volkert). The co-mentor (Perry) will provide the applicant with a clinical perspective on radiopharmaceutical development and how it relates to patient care. The formal training program will include a combination of didactic lectures, attendance at seminar presentations, practical training in the use of mouse models and oncology, practical training in the use of molecular and anatomic imaging techniques. Environment: The applicant will have access to Dr. Hoffman's laboratory (2,600 sq.ft.) fully equipped for the proposed synthesis and evaluation of the hypoxia enhanced Bombesin analogs. Also, the applicant will have access to the VA Animal Research Facility, Biomolecular Imaging Center, VA Nuclear Medicine Service, MU Cell and Immunobiology Core Facility and the MU Structural Biology Core. RELEVANCE: Currently in the United States, prostate cancer is the second leading cause of cancer related death in men. The diagnostic radiopharmaceuticals we will develop and evaluate will provide clinicians a crucial tool in the detection and staging of prostate cancer. The technology developed in this proposal may significantly increase the efficacy of diagnostic and therapeutic drugs in prostate and other forms of cancer.