Novel Bisphosphonate PET Probes for Myeloma Bone Disease

用于骨髓瘤骨病的新型双膦酸盐 PET 探针

基本信息

批准号：
10616547
负责人：
Kai Chen
金额：
$ 18.9万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-13 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10616547
关键词：
Anatomy Animals Area B cell differentiation Bone Diseases Bone Marrow Bone Marrow Involvement Bone Pain Bone Resorption Bone remodeling COVID-19 pandemic Cells Characteristics Chemistry Chest Clinic Clinical Clonal Expansion Complication Cyclotrons Data Detection Development Diagnosis Diagnostic Disadvantaged Disease Disease Progression Dose Early Diagnosis Emergency Situation Esters Femur Flare Fluorine Foundations Future Generations Goals Half-Life Healthcare Systems Hematologic Neoplasms Human Image Imaging technology In Situ Innate Bone Remodeling Investigation Label Laboratories Lesion Long-Term Care Lytic Lytic Metastatic Lesion Magnetic Resonance Imaging Malignant Neoplasms Measures Medical Imaging Modeling Molecular Molecular Weight Monitor Morbidity - disease rate Multiple Myeloma Mus Neurologic Deficit Newly Diagnosed Oncology Osteoblasts Osteogenesis Osteolysis Pain Pathological fracture Patients Pelvis Pharmaceutical Preparations Pharmacology Phase Physicians Physiological Plasma Cells Positron-Emission Tomography Preparation Procedures Process Production Quality of life Radiochemistry Radioisotopes Reaction Recording of previous events Reliability of Results Rodent Model Safety Sampling Site Skeletal Survey Solid Source Specificity Staging Symptoms Technology Time Translating Vertebral column X-Ray Computed Tomography X-Ray Medical Imaging bisphosphonate bone bone loss bone turnover clinical decision-making cost cranium design disability disease diagnostic fluorodeoxyglucose imaging agent imaging facilities imaging modality imaging probe improved in vivo individual patient innovation low dose computed tomography medical schools molecular imaging mortality novel novel therapeutic intervention personalized medicine radiochemical radiological imaging safety study small molecule success treatment optimization treatment response tumor

项目摘要

PROJECT SUMMARY/ABSTRACT Multiple myeloma (MM), a malignancy of mature plasma cells, is the second most common hematologic malignancy. Myeloma bone disease (MBD) is a devastating complication of MM. More than 80% of MM patients suffer from destructive bone lesions, leading to severe pain, pathologic fractures, mobility issues, and neurological deficits. MBD is not only a main cause of disability and morbidity in MM patients but also dramatically increases the cost of management. While recent advances in MM therapy have significantly increased the median survival of newly diagnosed patients, osteolytic lesions and their sequelae continue to be a major source of patient morbidity and mortality, and bone pain is the most frequent presenting symptom of MM patients. Rapid improvements in imaging technology now allow physicians to identify ever smaller osteolytic lesions and bone marrow abnormalities, however the clinical value of anatomic findings is not always clear. Therefore, earlier detection and more specific non-invasive assessment of treatment response is urgently needed, to assist in the clinical decision-making process and enable treatment optimization for the individual patient (“personalized medicine”). In this exploratory R21 application we propose novel 18F-BP-PET imaging probes to provide MBD patients a more sensitive measure of osteolytic lesions prompting them to take advantage of new treatment strategies known to improve survival in this group. It is our goal to show that these innovative BP-PET probes can overcome some of the disadvantages of current imaging strategies for MM and provide earlier diagnosis of MBD. Our long- term objective is to translate this new platform into the clinic as a more effective probe for imaging, detecting and staging MBD. Our innovative chemistry design offers rapid preparation (within one 18F half-life) of the proposed PET probes. Cold chemistry will be performed at the USC UPC laboratories by Dr. Charles McKenna and his team, and then elaborated for radiochemistry requirements with Dr. Kai Chen’s group at the USC HSC laboratories. All radiochemistry, including in situ cyclotron generation of the radioisotope 18F, as well as the in vivo animal studies and PET imaging will be performed under Dr. Kai Chen’s direction at the USC Molecular Imaging Center. The optimized radiosynthesis procedure will be validated in an automated synthesis module for future clinical production. To document the imaging efficacy of novel 18F-BP-PET probes, we will use 18F-FDG and 18F-NaF as control imaging agents in a rodent model of MM which reliably results in related bone lesions and compare them with our best novel probe to determine relative sensitivity, ability to detect early bone lesions, specificity and aptness to monitor treatment response. The successful completion of these proof-of-concept studies will serve as a solid foundation for next phase translational development.

项目概要/摘要多发性骨髓瘤 (MM) 是一种成熟浆细胞的恶性肿瘤，是第二常见的血液病骨髓瘤骨病（MBD）是 MM 患者的一种毁灭性并发症。遭受破坏性骨损伤，导致剧烈疼痛、病理性骨折、活动能力问题，以及神经功能缺陷不仅是 MM 患者残疾和发病的主要原因，而且也是造成 MM 患者残疾和发病的主要原因。虽然 MM 治疗的最新进展显着增加了治疗成本。新诊断患者的中位生存期，溶骨性病变及其后遗症仍然是主要来源骨痛是 MM 患者最常见的症状。成像技术的进步现在使医生能够识别更小的溶骨性病变和骨骼然而，骨髓异常的解剖学发现的临床价值并不总是明确的，因此更早。迫切需要对治疗反应进行检测和更具体的非侵入性评估，以协助临床决策过程并实现个体患者的治疗优化（“个性化药品”）。在这个探索性的 R21 应用中，我们提出了新型 18F-BP-PET 成像探针，为 MBD 患者提供对溶骨性病变更敏感的测量促使他们利用新的治疗策略我们的目标是证明这些创新的 BP-PET 探针可以克服这一问题。当前 MM 影像学策略的一些缺点，并提供我们长期的 MBD 早期诊断。长期目标是将这个新平台转化为临床，作为更有效的成像、检测和检测探针。我们的创新化学设计可快速制备（在一个 18F 半衰期内）所提议的物质。 PET 探针将由 Charles McKenna 博士和他的团队在 USC UPC 实验室进行。团队，然后与 USC HSC 的 Kai Chen 博士团队详细阐述了放射化学要求所有放射化学，包括放射性同位素 18F 的原位回旋加速器生成，以及原位回旋加速器生成。体内动物研究和 PET 成像将在南加州大学分子中心陈凯博士的指导下进行成像中心。优化的放射合成程序将在自动合成模块中进行验证。为了记录新型 18F-BP-PET 探针的成像功效，我们将使用 18F-FDG。和 18F-NaF 作为 MM 啮齿动物模型中的对照显像剂，可靠地导致相关骨病变并将它们与我们最好的新型探针进行比较，以确定相对灵敏度、检测早期骨病变的能力，监测治疗反应的特异性和适应性成功完成这些概念验证。研究将为下一阶段的转化发展奠定坚实的基础。