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

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，是第二常见的血液系统疾病。 恶性肿瘤骨髓瘤骨病（MBD）是MM的一种毁灭性并发症。超过80%的MM患者 遭受破坏性骨损伤，导致严重疼痛、病理性骨折、活动性问题，以及 神经缺陷MBD不仅是MM患者残疾和发病的主要原因，而且还显著地影响了MM患者的生活质量。 增加了管理成本。虽然MM治疗的最新进展显著增加了 新诊断患者的中位生存期、溶骨性病变及其后遗症仍然是导致骨坏死的主要原因。 的患者发病率和死亡率，骨痛是最常见的表现症状的MM患者。快速 成像技术的进步使医生能够识别更小的溶骨性病变和骨 然而，对于骨髓异常，解剖发现的临床价值并不总是清楚的。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 并且能够针对个体患者进行治疗优化（“个性化 医学”）。 这个IMAT-ITCR合作项目的目的是评估新型18F标记的双膦酸盐 (BP)用于临床前模型中MBD PET成像的探头，与现有的 显像剂，如18F-NaF。与此同时，我们将开发定量成像策略，以增强 MBD PET成像的准确性。这是一个高度跨学科的项目，桥接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病变。 该提案将基于由南方大学的PI，Chen博士和McKenna领导的合作 加州（USC）和圣路易斯华盛顿大学医学院（WUSM）的Shoghi博士。博士 McKenna将扩展他实验室中发现的新化学，以快速有效地引入氟 进入BP的P-C-P骨架，然后将与Chen博士的小组合作优化18 F放射性标记 procedure. Chen博士将验证新开发的18F标记的BP探针用于检测溶骨性 为了支持骨病变的定量成像，Shoghi博士将开发 定量成像管道，以提高来自骨髓的PET成像数据的准确性。 这些管道将增强临床前成像信息平台的能力， ITCR拨款，以加强成像数据分析。综合考虑，这些结果将为 最终的临床转化。

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.