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

Radium-223 联合治疗空间；

基本信息

批准号：
10356921
负责人：
Jeff M Michalski
金额：
$ 42.53万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
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/10356921
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 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 bone bone turnover castration resistant prostate cancer cohort data tools docetaxel dosimetry ds-DNA falls first-in-human fracture risk 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 phase III trial pre-clinical prostate cancer model rational design research clinical testing response side effect skills synergism tool treatment strategy uptake

项目摘要

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.

项目摘要 - 该R01提案解决了组合疗法的前进领域的关键需求 α粒子发射器。 radium-223二氯化物是α粒子发出的骨射射线循环范围。在骨转移性castrate抗性前列腺癌（BMCRPC）的患者的预后非常差，通过耐受性良好的安全性，这种疗法已提高了总体生存。对通过结合其他疗法，进一步改善了这些治疗的收益。但是，缺乏基础科学数据支持哪些组合可能会带来重大的好处，也可以为患者提供什么好处。这在两次组合试验中出现了意外的负面结果之后，赤字已使赤字浮出水面。这需要更好地了解如何将α粒子发射器与其他疗法相结合是重要的仅除了辐射223之外发射剂，其中许多正在进入临床评估。在这里，我们对改善疾病部位的药物递送的意义进行了多次独立研究，避免脱离目标的时间，并更深入地了解积极和负面结果的基础组合。该提案预测在广泛的临床前研究和新兴的临床发现中并在技术先进的疾病模型中进行了测试，这些模型概括了人类BMCRPC的关键特征。在具体目标1（S.A.1）我们测试了将223RA与批准的药物调节剂，可改善对骨骼的递送并减少靶向摄入剂。 S.A.2将我们引人入胜的试验数据扩展到分子基础，以替代乙酸阿比罗酮的结合和223ra;由于骨折增加和死亡风险，该组合的临床评估停止了。在 S.A.3我们研究了DNA修复缺陷对受控系统中赖赖-223响应的影响在有限的患者队列中有趣的发现，对223RA的反应得到了改善。我们发现的影响将是直接的；我们指示避免毒性的分子机制的试验数据，预测最有可能从223RA中受益的人，并确定可能产生严重侧面的组合效果。长期，这些数据和工具在激励改进管理方面具有相当大的重要性成千上万的骨转移性疾病患者。多学科团队的技能和知识核医学，辐射肿瘤学，放射化学，临床前疾病模型的专家病理确保实现提出的目标的最高可能性。