Treatment Effects on Tumor 18F-Choline Metabolism in Advanced Prostate Cancer

描述（由申请人提供）：转移激素难治性前列腺癌（HRPC）患者的预后较差，尽管采用现代化疗，中位生存期为16至18个月。多西他赛，单独或与其他化疗药物联合，是目前最有效的治疗HRPC的方法。然而，由于多西他赛仅能提供适度的生存益处，因此需要更有效的药物。不幸的是，HRPC在成像和量化疾病进展方面的困难继续阻碍药物开发和临床试验。分子成像技术，如正电子发射断层扫描/计算机断层扫描（PET/CT）可能为临床试验和临床实践提供新的方法来测量肿瘤对治疗的反应。氟-18氟胆碱（18f -胆碱）是一种正在研究的PET示踪剂，在激素难治性和激素原发性前列腺癌的成像中显示出相当大的前景。在初步研究中，多西紫杉醇已被证明可以调节转移性肿瘤对18f -胆碱的摄取。我们的目的是确定肿瘤18f -胆碱摄取的这些治疗相关变化的测量是否可以用于衡量HRPC的治疗反应。研究多西他赛和雄激素调控对18f -胆碱代谢的短期影响的R21提案将解决纵向研究设计相关的方方法论问题，该研究评估基于PET/ ct的18f -胆碱测量作为HRPC化疗患者生存和疼痛结局的替代标志物。我们的目的是：1)研究多西紫杉醇治疗HRPC后肿瘤18f -胆碱摄取变化与前列腺特异性抗原水平变化之间的关系；2)研究多西紫杉醇化疗期间肿瘤18f -胆碱摄取变化的时间过程；3)研究抗雄激素药物停药对激素不敏感的前列腺癌肿瘤18f -胆碱摄取的影响。在满足这些目标的基础上，进行纵向研究以评估18f -胆碱PET/CT作为HRPC肿瘤反应指标的可行性。追求这些目标也可能导致一种技术，以帮助治疗和调查多西紫杉醇和激素耐药性的HRPC。

DESCRIPTION (provided by applicant): The prognosis for patients with metastatic hormone refractory prostate cancer (HRPC) is poor with a median survival of 16 to 18 months despite modern chemotherapy. Docetaxel, alone or in combination with other chemotherapeutic agents, is currently the most active treatment available for HRPC. However, because docetaxel confers only a modest survival benefit, there is a need for more effective drugs. Unfortunately, difficulties in imaging and quantifying disease progression in HRPC have continued to hinder drug development and clinical trials. Molecular imaging techniques such as positron emission tomography/ computed tomography (PET/CT) may contribute novel ways of measuring tumor responses to therapy for both clinical trials and clinical practice. Fluorine-18 fluorocholine (18F-choline) is an investigational PET tracer that has shown considerable promise for imaging hormone-refractory and hormone-naive prostate cancer. In pilot studies, docetaxel has been shown to modulate the uptake of 18F-choline by metastatic tumors. Our goal is to determine whether measurement of these treatment-associated changes in tumor 18F-choline uptake can be used to gauge therapeutic response in HRPC. This R21 proposal to study the short-term effects of docetaxel and androgen hormone manipulation on 18F-choline metabolism will resolve methodological issues relevant to the design of a longitudinal study evaluating 18F-choline PET/CT-based measures as surrogate markers for survival and pain outcomes in patients with HRPC receiving chemotherapy. Our aims are: 1) examine the relationship between changes in tumor 18F-choline uptake and changes in prostate specific antigen level in response to docetaxel treatment of HRPC, 2) examine the time course by which changes in tumor 18F-choline uptake occur during docetaxel chemotherapy, and 3) examine the effects of anti-androgen drug withdrawal on tumor 18F-choline uptake in prostate cancer that is becoming hormone-insensitive. The feasibility of a longitudinal study to evaluate 18F-choline PET/CT as a tumor response measure in HRPC will be based on meeting these aims. Pursuit of these aims may also result in a technique to aid in treating and investigating docetaxel and hormone resistance in HRPC. PUBLIC HEALTH RELEVANCE: Despite modern advancements in chemotherapy, the prognosis for patients with metastatic prostate cancer is poor and virtually all deaths from prostate cancer are due to metastatic disease. Difficulties in imaging and quantifying the disease continue to create barriers for new drug development and clinical trials. We propose to investigate a method of molecular imaging that in concert with conventional imaging could enhance the ability to detect, monitor, and predict the effects of chemotherapy on metastatic tumors, to the point that effective treatments can be customized based on the tumor characteristics of each individual patient.