The Radium-223 Combination Therapy Space; Improving Response and Clarifying Toxicities

Radium-223 联合治疗空间；

• 批准号: 9973321
• 负责人: Jeff M Michalski
• 金额: $ 51.58万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9973321
• 关键词: Acetates; Active Sites; Address; Adverse event; Alpha Particle Emitter; Alpha Particles; Amiloride; Antitumor Response; Autoradiography; Basic Science; Biodistribution; Biological; Biomechanics; Biopsy; Blood; Bone remodeling; Cancer Etiology; Cancer Patient; Cells; Cessation of life; Chemistry; Clinical; Combined Modality Therapy; DNA Repair; DNA Repair Inhibition; Data; Defect; Deposition; Diagnosis; Discipline of Nuclear Medicine; Disease; Disease model; Disseminated Malignant Neoplasm; Distress; Diuretics; Dose; Drug Delivery Systems; Drug Kinetics; Ensure; Enterocytes; Exhibits; FDA approved; Fracture; Frequencies; Gastrointestinal tract structure; Gene Expression; Goals; Health; Histologic; Histopathology; Human; Image; In Vitro; Investigation; Knowledge; Laboratories; Lesion; Malignant Neoplasms; Malignant neoplasm of prostate; Medical; Metastatic Neoplasm to the Bone; Modeling; Molecular; Monitor; Organ; Organoids; Outcome; Pathology; Patient observation; Patients; Pharmaceutical Preparations; Pharmacology; Physics; Pre-Clinical Model; Quality of life; Radiation Oncology; Radiation therapy; Radiochemistry; Radioisotopes; Radiology Specialty; Radionuclide therapy; Radium; Reporting; Research; Safety; Serum; Site; System; Testing; Therapeutic; Time; Tissues; Toxic effect; Toxicology; Treatment Efficacy; Validation; Work; abiraterone; bone; bone turnover; castration resistant prostate cancer; cohort; data tools; design; docetaxel; dosimetry; ds-DNA; falls; first-in-human; fracture risk; gastrointestinal; genetic analysis; genomic data; high throughput screening; improved; improved outcome; in vivo; inhibitor/antagonist; innovation; insight; interest; irradiation; male; men; monolayer; mortality risk; multidisciplinary; non-invasive imaging; novel strategies; novel therapeutics; osteogenic; outcome forecast; particle therapy; patient subsets; phase III trial; pre-clinical; prostate cancer model; research clinical testing; response; side effect; skills; synergism; tool; treatment strategy; uptake

PROJECT SUMMARY – This R01 proposal addresses a critical need in the advancing field of combination therapies involving potent alpha particle emitters. Radium-223 dichloride is an alpha particle emitting bone-seeking radionuclide range. In patients with bone metastatic castrate resistant prostate cancer (bmCRPC), which has a very poor prognosis, this therapy has achieved improved overall survival with a well-tolerated safety profile. There is great interest in further improving these treatment gains through combination with other therapies. However, there is a lack of basic science data to support which combinations may provide a significant benefit nor for which patients. This deficit has been brought into stark relief following unexpected negative outcomes in two combination trials. The need for a better understanding of how to combine alpha particle emitters with other therapies is significant beyond Radium-223 alone, as its approval has helped to generate considerable interest for other alpha particle emitting agents, many of which are entering clinical evaluation at this time. Here, we undertake multiple, independent investigations of means to improve drug delivery to disease sites, spare off-target tissues, and to more deeply understand the basis for positive and negative outcomes of combinations. This proposal is predicated on extensive preclinical investigation and emergent clinical findings and are tested in technically advanced models of disease that recapitulate key features of human bmCRPC. In Specific Aim 1 (S.A.1) we test the long term safety profile and anti-metastatic efficacy of combining 223Ra with an approved pharmacological modulator that improves drug delivery to the bone and reduces off-target uptake. S.A.2 extends our compelling pilot data into the molecular basis for the lethal combination of abiraterone acetate and 223Ra; the clinical evaluation of this combination was halted due to increased fracture and risk of death. In S.A.3 we investigate the impact of DNA repair defects on Radium-223 responses in controlled systems following intriguing findings in a limited patient cohort with improved responses to 223Ra. The impact of our findings will be immediate; our pilot data indicate molecular mechanisms to avoid toxicity, to predict those most likely to benefit from 223Ra, as well as identify combinations that may produce severe side effects. Long-term, these data and tools have considerable import in motivating improved management of the tens of thousands of patients with bone metastatic disease. The skills and knowledge of a multidisciplinary team of experts in the fields of nuclear medicine, radiation oncology, radiochemistry, preclinical disease models and pathology ensures the highest likelihood of achieving the proposed aims.

项目概要 – 该 R01 提案解决了涉及强效联合疗法的先进领域的关键需求 阿尔法粒子发射器。二氯化镭 223 是一种发射骨寻踪放射性核素系列的 α 粒子。在 患有骨转移性去势抵抗性前列腺癌（bmCRPC）的患者，其预后非常差， 该疗法提高了总体生存率，且安全性良好。人们对此非常感兴趣 通过与其他疗法相结合，进一步提高这些治疗效果。然而，目前还缺乏 基础科学数据支持哪些组合可以提供显着的益处或为哪些患者提供显着益处。这 在两项联合试验中出现意外的负面结果后，赤字已得到明显缓解。这 迫切需要更好地了解如何将 α 粒子发射器与其他疗法结合起来 除了镭 223 之外，它的批准也引起了人们对其他 α 粒子的极大兴趣 发射剂，其中许多目前正在进入临床评估。 在这里，我们对改善疾病部位药物输送的方法进行了多项独立调查， 避免脱靶组织，并更深入地了解积极和消极结果的基础 组合。该提案基于广泛的临床前研究和紧急临床发现 并在技术先进的疾病模型中进行测试，概括了人类 bmCRPC 的关键特征。在 具体目标 1 (S.A.1) 我们测试了 223Ra 与 一种经批准的药理学调节剂，可改善药物向骨骼的输送并减少脱靶吸收。 S.A.2 将我们令人信服的试验数据扩展到醋酸阿比特龙致命组合的分子基础 和223Ra；由于骨折和死亡风险增加，该组合的临床评估已停止。在 S.A.3 我们研究了 DNA 修复缺陷对受控系统中 Radium-223 反应的影响，如下 在有限的患者队列中得到了有趣的发现，对 223Ra 的反应有所改善。 我们的研究结果将产生立竿见影的影响；我们的试验数据表明了避免毒性的分子机制， 预测那些最有可能从 223Ra 中受益的人，以及识别可能产生严重副作用的组合 影响。从长远来看，这些数据和工具对于推动改进管理具有相当重要的意义。 数以万计的骨转移患者。多学科团队的技能和知识 核医学、放射肿瘤学、放射化学、临床前疾病模型和 病理学确保实现拟议目标的最大可能性。