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成为控制通常严重的、 治疗引起的毒性和阻止癌症进展会导致毒性增加。 联合治疗方案，直到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，将辐射传递到目标细胞。 α粒子发射体 RPT (αRPT) 是一种全新的、根本不同的治疗方式，可以打破这一点 它是唯一能够向播散性癌症转移提供高效 α 粒子的方式。 从根本上讲，它是一种辐射传输方式，所传输的辐射类型不易受到辐射的影响。 通过生物（或途径抑制）治疗观察到的耐药机制或意外副作用，以及 尽管存在这些关键差异，αRPT 仍在长期多周期方案中进行。 这严重损害了这种治疗方式的潜在疗效，这在很大程度上是因为严格的、 不存在经过验证的 α 发射体剂量测定方法，此类方法可以预测潜力。 个别患者的正常器官毒性，无需因毒性而延长治疗时间 我们的主要目标是：1）开发和测试剂量测定方法，以实现精确度。 基于医学/治疗计划的癌症治疗 αRPT 以及 2) 获得所需的理解 优化涉及 αRPT 的联合疗法 支持该计划项目资助的假设如下： 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肿瘤 癌症；它对传统耐药机制的敏感性要低得多，它也适合剂量测定驱动。 2. 目前实施的 αRPT 尚未发挥其潜力。 已证明制定 RPT 计划可显着提高长期生存率 3. 没有一种癌症治疗方法。 治疗方式具有治愈性，但患者的潜在治疗反应和毒性各不相同。 尽管机制研究被用来指向合理的方向，但不可避免地要与其他疗法结合起来。 就每种组合的顺序和数量而言，临床试验仍然主要是经验性的 剂量测定和放射生物学驱动的方法将大大缩小人类的范围。 考虑到这些假设，我们的总体目标是开发方法和方法。 研究如何最好地将 RPT 实施从“放射性化疗范式”过渡到 这些基本假设与放射治疗计划更加一致。 该计划项目中提出的工作非常简单：剂量测定已被证明可以改善结果。 RPT 剂，但 α 发射体的剂量测定很难，该计划项目的五年支持将使 αRPT 成为可能。 剂量测定很容易广泛实施，从而提高目前无法治愈的癌症的生存率。