IMAT‐ITCR Collaboration: Preclinical Evaluation of Novel Bisphosphonate PET Probes for Myeloma Bone Disease

项目摘要/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 恶毒。骨髓瘤是多发性骨髓瘤的严重并发症，超过80%的多发性骨髓瘤患者 遭受破坏性的骨骼损伤，导致严重疼痛、病理性骨折、行动不便以及 神经缺陷。多发性肌萎缩侧索硬化症不仅是多发性骨髓瘤患者残疾和发病的主要原因，而且 增加了管理成本。虽然多发性骨髓瘤治疗的最新进展显著增加了 新诊断患者的中位存活率、溶骨性病变及其后遗症仍是主要来源 骨痛是多发性骨髓瘤患者最常见的症状。快速 成像技术的进步现在使医生能够识别出越来越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，早些时候 迫切需要对治疗反应进行检测和更具体的非侵入性评估，以帮助 临床决策过程，并实现针对个别患者的治疗优化(个性化 医学“)。 这个IMAT-ITCR合作项目的目的是评估新型18F标记双膦酸盐 (BP)用于临床前模型中MBD的PET成像的探针，与现有的相比具有潜在的显著优势 显像剂，如18F-NaF。同时，我们将制定定量成像策略，以增强 MBD正电子发射计算机断层成像的准确性。这是一个高度跨学科的项目，将BP化学、放射化学、 和定量PET成像来检测MM动物模型中的早期溶骨性损害。 提案将基于南方大学的PI、陈博士和麦肯纳博士领导的合作 圣路易斯华盛顿大学医学院(WUSM)的Shoghi博士说。Dr。 麦肯纳将扩展他的实验室中发现的新化学物质，以快速有效地引入氟 进入BP的P-C-P主干，然后将与陈博士的团队合作，优化18F放射性标记 程序。陈博士将验证新开发的18F标记BP探针用于检测骨溶解 MM啮齿动物模型中的病变为了支持骨骼病变的定量成像，Shoghi博士将开发 定量成像管道，以提高源自骨髓的PET成像数据的准确性。 这些管道将增强通过以下方式开发的临床前成像信息学平台的能力 ITCR拨款用于增强成像数据分析。综上所述，这些结果将奠定坚实的基础 用于终极临床翻译。

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 are urgently needed, to assist in the clinical decision-making process and enable treatment optimization for the individual patient (“personalized medicine”). The objective of this IMAT-ITCR collaborative project is to evaluate novel 18F-labeled bisphosphonate (BP) probes for PET imaging of MBD in preclinical models, with potentially significant advantages over existing imaging agents, such as 18F-NaF. In parallel, we will develop quantitative imaging strategies to enhance the accuracy of PET imaging of MBD. It is a highly interdisciplinary project, bridging BP chemistry, radiochemistry, and quantitative PET imaging to detect early osteolytic lesions in animal models of MM. Implementation of this proposal will be based on a collaboration led by the PIs, Drs. Chen and McKenna at the University of Southern California (USC) and Dr. Shoghi at the Washington University School of Medicine (WUSM) in St. Louis. Dr. McKenna will expand the new chemistry discovered in his laboratory to rapidly and efficiently introduce fluorine into the P-C-P backbone of BP and then will work with Dr. Chen's group to optimize the 18F radiolabeling procedure. Dr. Chen will validate the newly developed 18F-labeled BP probes for the detection of osteolytic lesions in rodent models of MM. To support quantitative imaging of bone lesions, Dr. Shoghi will develop quantitative imaging pipelines to enhance the accuracy of PET imaging data derived from the bone marrow. These pipelines will enhance the capabilities of the preclinical imaging informatics platform developed through the ITCR grant to enhance the imaging data analysis. Taken together, the results will establish a solid foundation for ultimate clinical translation.