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: 10405086
• 负责人: Kai Chen
• 金额: $ 22.68万
• 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 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10405086
• 关键词: Anatomy; Animals; Area; B cell differentiation; Bone Diseases; Bone Marrow; Bone Marrow Involvement; Bone Pain; Bone Resorption; Bone neoplasms; Bone remodeling; COVID-19 pandemic; Cells; Characteristics; Chemistry; Chest; Clinic; Clinical; Clonal Expansion; Complication; Cyclotrons; Data; Detection; Development; Diagnosis; Diagnostic; Disadvantaged; Disease; Disease Management; Disease Progression; Dose; Early Diagnosis; Emergency Situation; Emission-Computed Tomography; Esters; Femur; Flare; Fluorine; Foundations; Future; Generations; Goals; Gold; 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; 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; base; 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; personalized medicine; radiochemical; radiological imaging; safety study; small molecule; success; treatment optimization; treatment response; treatment strategy

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.

项目摘要/摘要 多发性骨髓瘤（MM）是成熟浆细胞的恶性肿瘤，是第二个最常见的血液学 恶性。骨髓瘤骨病（MBD）是MM的毁灭性并发症。超过80％的MM患者 患有破坏性的骨骼病变，导致剧烈疼痛，病理骨折，流动性问题和 神经缺陷。 MBD不仅是MM患者的残疾和发病率的主要原因 增加管理成本。尽管MM治疗的最新进展显着增加了 新诊断的患者，溶裂性病变及其后遗症的中位生存期继续是主要来源 患者的发病率和死亡率以及骨痛是MM患者最常见的症状。迅速的 影像技术的改进现在使医生可以识别较小的骨化病变和骨骼 骨髓异常，但是解剖学发现的临床价值并不总是很清楚。因此，较早 迫切需要检测和更具体的治疗反应评估，以帮助 临床决策过程并为个别患者提供治疗优化（“个性化） 药品”。 在此探索性R21应用中，我们提出了新型18F-BP-PET成像问题为MBD患者提供 对溶性病变的更敏感的测量促使他们利用新的治疗策略 已知可以改善这一组的生存。我们的目标是表明这些创新的BP-PET探针可以克服 当前对MM的成像策略的灾难，并提供了MBD的较早诊断。我们的长期 术语目标是将这个新平台转化为诊所，以作为对成像，检测和 分期MBD。我们的创新化学设计提供了拟议中的快速准备（在一个18f半衰期之内 宠物问题。 Charles McKenna博士和他的 团队，然后与USC HSC的Kai Chen博士小组详细阐述放射化学要求 实验室。所有放射化学，包括放射性同位素18F的原位回旋体生成以及IN 体内动物研究和宠物成像将在凯·陈（Kai Chen）博士的指导下在USC分子上进行 成像中心。优化的放射合成过程将在自动合成模块中验证 未来的临床生产。为了记录新型18F-BP-PET探针的成像效率，我们将使用18F-FDG 在MM的啮齿动物模型中，18F-NAF作为对照成像剂，可靠地导致相关的骨骼病变 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，检测早期骨骼病变的能力， 特异性和适当的监测治疗反应。这些概念证明的成功完成 研究将成为下一阶段转化发展的坚实基础。