Imaging, Dosimetry and Radiobiology for α-particle Emitter Radiopharmaceutical Therapy

α 粒子发射器放射性药物治疗的成像、剂量测定和放射生物学

• 批准号: 10713709
• 负责人: George Sgouros
• 金额: $ 262.39万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-19 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10713709
• 关键词: Adoption; Alpha Particle Emitter; Alpha Particles; Biological; Cancer Biology; Cancer Patient; Caring; Cell surface; Cells; Clinical Trials; Clinical Trials Design; Combined Modality Therapy; Conformal Radiotherapy; DNA; Data; Disease Progression; Disseminated Malignant Neoplasm; Dose; Drug Kinetics; Electrons; Equilibrium; Evaluation; High-LET Radiation; Human Experimentation; Image; Kinetics; Malignant Neoplasms; Measures; Methodology; Methods; Modality; Modeling; Mutation; Neoplasm Metastasis; Normal tissue morphology; Organ; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Physics; Predisposition; Program Research Project Grants; Radiation; Radioactive; Radiobiology; Radiopharmaceuticals; Regimen; Rest; Risk; Scheme; Testing; Therapeutic; Therapeutic Agents; Three-Dimensional Imaging; Time; Toxic effect; Translating; Treatment Efficacy; Treatment-related toxicity; Tumor Biology; Tumor Cell Biology; Tumor Tissue; Work; absorption; biomarker identification; cancer therapy; cell killing; chemotherapy; dosimetry; effective therapy; improved; improved outcome; individual patient; meter; particle; precision medicine; prevent; programs; quantitative imaging; radiation delivery; repaired; resistance mechanism; response; side effect; synergism; treatment planning; treatment responders; treatment response; trend; tumor; tumor progression

Treatment for almost all patients with metastatic cancer has become a balance between managing often severe, treatment-induced toxicity and preventing cancer progression. Progression leads to increasingly toxic combination regimens until the patient succumbs either to treatment toxicity or to disease progression. Radiopharmaceutical therapy (RPT) is an emerging treatment modality that delivers radiation to targeted cells. Alpha-particle-emitter RPT (αRPT) is a new and fundamentally different therapeutic modality that can break this cycle. It is the only modality that can deliver highly potent, α-particles to disseminated cancer metastases. Fundamentally, it is a radiation delivery modality. The radiation type delivered is far less susceptible to the resistance mechanisms or unanticipated side-effects observed with biologic (or pathway inhibition) therapy and chemotherapy. Despite these key differences, αRPT is being administered in a prolonged multi-cycle scheme that severely compromises the potential efficacy of this treatment modality. In large part, this is because rigorous, validated dosimetry methods for α-emitters do not exist. Such methods would make it possible to project potential normal organ toxicity for individual patients so that treatment need not be prolonged for the sake of toxicity evaluation. Our primary objectives are: 1) to develop and test dosimetry methodologies that will enable precision medicine/treatment-planning-based αRPT for cancer therapy and 2) to gain the understanding needed to optimize combination therapies involving αRPT. The hypotheses underpinning this program project grant are as follows: 1. αRPT is a systemic cancer therapy modality that is particularly applicable to targeting metastatic cancer; it is far less susceptible to conventional resistance mechanisms. It is also amenable to dosimetry-driven treatment planning. 2. As currently implemented αRPT is not achieving its potential. Dosimetry-driven treatment planning for RPT has been demonstrated to substantially improve long-term survival. 3. No one cancer treatment modality is curative, and patients differ in their potential therapeutic response and toxicity. Promising agents are inevitably combined with other therapeutics. Although mechanistic studies are used to point towards rational combinations, clinical trials continue to be largely empirical in terms of the sequencing and amount of each administered drug. A dosimetry and radiobiology-driven approach will substantially reduce the scope of human experimentation. Considering these hypotheses, our overall objective is to develop methodologies and investigate how best to transition RPT implementation from that of a “radioactive chemotherapy paradigm” to one more closely aligned with treatment planning for radiation delivery. These foundational hypotheses motivate the work proposed in this program project. Put very simply: dosimetry has been proven to improve outcome for RPT agents but dosimetry for alpha-emitters is hard. Five years support of this program project will make αRPT dosimetry easy enough to implement widely and thereby improve survival for currently incurable cancers.

几乎所有转移性癌症患者的治疗已经成为一种平衡， 治疗诱导的毒性和预防癌症进展。进展导致毒性越来越大 组合方案直至患者死于治疗毒性或疾病进展。 放射性药物治疗（RPT）是一种新兴的治疗方式，将辐射传递到靶细胞。 α粒子发射器RPT（αRPT）是一种新的，从根本上不同的治疗方式，可以打破这一点 周期它是唯一一种可以将高效α粒子输送到播散性癌症转移灶的方法。 从根本上说，它是一种辐射输送方式。所提供的辐射类型远不容易受到 生物（或途径抑制）治疗中观察到的耐药机制或非预期副作用， 化疗尽管存在这些关键差异，但αRPT仍以延长的多周期方案给药 这严重损害了这种治疗方式的潜在功效。在很大程度上，这是因为严格， 目前还没有经过验证的α-发射体剂量测定方法。这种方法将使预测潜力成为可能 个体患者的正常器官毒性，因此无需因毒性而延长治疗 评价我们的主要目标是：1）开发和测试剂量测定方法， 用于癌症治疗的基于药物/治疗计划的αRPT; 2）获得所需的理解， 优化涉及αRPT的联合治疗。支持该计划项目赠款的假设如下 如下：1.αRPT是一种全身性癌症治疗方式，特别适用于靶向转移性 癌症;它对传统的耐药机制不太敏感。它也适用于剂量测定驱动 治疗计划2.目前实施的αRPT未发挥其潜力。剂量驱动治疗 已证明RPT计划可显著提高长期生存率。3.没有一个癌症治疗 治疗方式是治愈性的，患者在潜在的治疗反应和毒性方面存在差异。有前途的代理商是 不可避免地与其他疗法相结合。尽管机械论的研究被用来指向理性 联合用药，临床试验仍然主要是经验性的排序和数量方面的每一个 给药。剂量测定和放射生物学驱动的方法将大大减少人类的辐射范围。 实验考虑到这些假设，我们的总体目标是开发方法， 研究如何最好地将RPT实施从“放射性化疗范例”过渡到 一个更紧密地与用于放射递送的治疗计划对准。这些基本假设激发了 本计划项目中提出的工作。简单地说：剂量测定已被证明可以改善 RPT剂，但α-发射体的剂量测定是困难的。该计划项目的五年支持将使αRPT 剂量测定易于广泛实施，从而提高目前无法治愈的癌症的生存率。