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

Radium-223 联合治疗空间；

• 批准号: 10577850
• 负责人: Jeff M Michalski
• 金额: $ 42.9万
• 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/10577850
• 关键词: Ablation; 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; Physics; Pre-Clinical Model; Prognosis; 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; absorption; bone; bone turnover; castration resistant prostate cancer; cohort; docetaxel; dosimetry; ds-DNA; falls; first-in-human; gastrointestinal; genetic analysis; genomic data; high throughput screening; improved; improved outcome; in vivo; inhibitor; innovation; insight; interest; irradiation; male; men; monolayer; mortality risk; multidisciplinary; non-invasive imaging; novel strategies; novel therapeutics; osteogenic; particle therapy; patient subsets; pharmacologic; phase III trial; pre-clinical; prostate cancer model; rational design; 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.

项目总结- 这份R01提案解决了先进的联合疗法领域中的一项关键需求，该领域包括 阿尔法粒子发射器。Re-223二氯化物是一种发射寻骨放射性核素范围的阿尔法粒子。在……里面 骨转移性去势抵抗前列腺癌(BmCRPC)患者预后非常差， 这种疗法以良好的耐受性实现了总存活率的提高。人们对……很感兴趣 通过与其他疗法相结合，进一步改善这些治疗效果。然而，目前还缺乏 基础科学数据支持哪些组合可能提供显著的益处，也不支持哪些患者。这 在两个联合试验中出现意想不到的负面结果后，赤字已得到明显缓解。这个 有必要更好地了解如何将阿尔法粒子发射器与其他疗法相结合 除了Re-223之外，因为它的批准有助于引起人们对其他阿尔法粒子的相当大的兴趣 发射剂，其中许多目前正在进入临床评估。 在这里，我们对改善向疾病地点输送药物的方法进行多项独立的调查， 保留靶外组织，并更深入地了解 组合。这项建议是建立在广泛的临床前研究和紧急临床发现的基础上的 并在技术先进的疾病模型中进行测试，这些模型概括了人类bmCRPC的关键特征。在……里面 特异性目标1(S.A.1)：我们测试了223Ra和联合用药的长期安全性和抗转移疗效 一种经批准的药理调节剂，可改善药物向骨骼的输送并减少非靶向摄取。 S.A.2将我们令人信服的试点数据扩展到醋酸阿比特龙致命组合的分子基础上 和223Ra；由于骨折增加和死亡风险增加，该组合的临床评估停止。在……里面 S.A.3我们研究了DNA修复缺陷对以下受控系统中Radium-223反应的影响 在对223Ra有改善反应的有限患者队列中，有趣的发现。 我们的发现的影响将是立竿见影的；我们的试点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，以及确定可能产生严重副作用的组合 效果。从长远来看，这些数据和工具在激励改善对 数以万计的骨转移疾病患者。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 病理学确保了实现拟议目标的最高可能性。