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严重管理的平衡， 治疗引起的毒性和预防癌症的进展。进展导致剧毒越来越多 联合方案直到患者屈服于治疗毒性或疾病进展。 放射药物治疗（RPT）是一种紧急治疗方式，可为靶向细胞提供辐射。 α粒子发射极rpt（αRPT）是一种新的且根本不同的治疗方式，可以打破这一点 循环。这是唯一可以向传播癌症转移酶传递高潜力的α粒子的方式。 从根本上讲，这是一种辐射传递方式。传递的辐射类型不太容易受到 使用生物（或途径抑制）疗法观察到的耐药机制或意外副作用 化学疗法。尽管有这些关键差异，但仍在延长的多周期方案中施用αRPT 这严重损害了这种治疗方式的潜在有效性。在很大程度上，这是因为严格 不存在验证的α-发射体的剂量测定方法。这样的方法将使潜在的投影成为可能 正常器官对个别患者的毒性，因此不必为了毒性而延长治疗 评估。我们的主要目标是：1）开发和测试将启用精确度的剂量测定方法 医学/基于治疗计划的αRPT用于癌症治疗，2）获得所需的理解 优化涉及αRPT的组合疗法。该计划项目赠款的基础的假设是 以下内容：1。αRPT是一种全身性癌症治疗方式，特别适用于靶向转移 癌症;它不太容易受到常规抗性机制的影响。它也适合剂量驱动 治疗计划。 2。由于目前实施的αRPT并未达到其潜力。剂量驱动的处理 已证明对RPT的计划可大大改善长期生存。 3。没有一种癌症治疗 模态是治愈性的，患者的潜在治疗反应和毒性有所不同。有希望的代理人 不可避免地与其他治疗剂结合在一起。尽管机械研究被用来指向理性 组合，临床试验在每种测序和数量方面仍然在很大程度上是经验的 管理药物。剂量测定和放射生物学驱动的方法将大大减少人类的范围 实验。考虑到这些假设，我们的总体目标是开发方法和 调查如何最好地将RPT实施从“放射性化疗范式”转变为 一个与辐射输送的治疗计划紧密相符。这些基本假设激励 该计划项目中提出的工作。简而言之：剂量测定已被证明可以改善结果 RPT代理，但对于α发射器的剂量测定很难。该计划项目的五年支持将使αRpt 剂量法易于实施，从而改善了目前无法治愈的癌症的生存。