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

项目概要- 该R01提案解决了在涉及强效抗肿瘤药物的联合疗法的发展领域中的关键需求。 阿尔法粒子发射器镭-223二氯化物是一种发射α粒子的骨导向放射性核素。在 患有骨转移性去势抵抗性前列腺癌（bmCRPC）的患者，其具有非常差的预后， 该疗法已经实现了改善的总存活率，并且具有良好耐受的安全性。有很大的兴趣， 通过与其他疗法的组合进一步改善这些治疗收益。然而，缺乏 基础科学数据，以支持哪些组合可能提供显着的好处，也不为哪些患者。这 在两项联合试验中出现意想不到的负面结果后，这一缺陷得到了明显的缓解。的 我们需要更好地理解如何将联合收割机α粒子发射器与其他疗法相结合，这是非常重要的 除了镭-223之外，它的批准有助于对其他α粒子产生相当大的兴趣 发射剂，其中许多正在进入临床评价在这个时候。 在这里，我们进行多个，独立的调查手段，以改善药物输送到疾病的网站， 保留脱靶组织，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，这些模型概括了人bmCRPC的关键特征。在 具体目标1（S.A.1），我们测试了223Ra与223Ra组合的长期安全性特征和抗转移功效。 一种批准的药理学调节剂，可改善药物向骨的递送并减少脱靶摄取。 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死组合的分子基础 和223Ra;由于骨折和死亡风险增加，该组合的临床评价停止。在 S.A.3我们研究了DNA修复缺陷对受控系统中镭-223反应的影响， 在对223Ra的反应改善的有限患者队列中的有趣发现。 我们的研究结果将立即产生影响;我们的初步数据表明了避免毒性的分子机制， 预测那些最有可能从223 Ra中受益的人，以及确定可能产生严重副作用的组合。 方面的影响.从长远来看，这些数据和工具在促进改善对环境的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、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。

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.