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

• 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
• 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

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 恶性肿瘤。骨髓瘤骨病 (MBD) 是 MM 的一种破坏性并发症。超过80%的MM患者 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。 MBD 不仅是 MM 患者残疾和发病的主要原因，而且还显着 增加管理成本。虽然 MM 治疗的最新进展显着增加了 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。迅速的 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 骨髓异常，然而解剖学结果的临床价值并不总是明确的。因此，较早 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 已知可以提高该群体的生存率。我们的目标是证明这些创新的 BP-PET 探针可以克服 当前 MM 影像学策略的一些缺点，并提供 MBD 的早期诊断。我们的长期 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。 分期MBD。我们的创新化学设计可快速制备（在一个 18F 半衰期内）拟议的 PET 探针。 Charles McKenna 博士及其团队将在南加州大学 UPC 实验室进行冷化学实验 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 实验室。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 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 影像中心。优化的放射合成程序将在自动合成模块中进行验证 未来的临床生产。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。