Dose-Response in Radionuclide Therapy

放射性核素治疗的剂量反应

• 批准号: 9594370
• 负责人: Robert Francois Hobbs
• 金额: $ 68.47万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9594370
• 关键词: Address; Alpha Particle Emitter; Alpha Particles; Anatomy; Antibodies; Area; Beta Particle; Binding; Biological; Cancer Patient; Cells; Clinic; Clinical Trials; Computer software; Coupled; Credentialing; DNA; Data; Dose; Dose-Limiting; Drug Kinetics; Evaluation; External Beam Radiation Therapy; Formulation; Grant; Image; In Vitro; Kidney; Label; Linear Energy Transfer; Magnetic Resonance Imaging; Maps; Measures; Methodology; Methods; Modality; Modeling; Normal tissue morphology; Organ; Outcome; Patients; Peptides; Phase; Positron-Emission Tomography; Publishing; Radiation therapy; Radioactive; Radionuclide therapy; Radiopharmaceuticals; Relative Biological Effectiveness; Resistance; Risk; Samarium 153; Therapeutic; Time; Tissues; To specify; Toxic effect; Tracer; Treatment Efficacy; United States National Institutes of Health; Work; base; cancer therapy; chemotherapy; computerized tools; dosimetry; experience; in vivo; individual patient; neoplastic cell; novel; osteosarcoma; particle; response; single photon emission computed tomography; small molecule; treatment optimization; treatment planning; tumor

Dose-Response in Radionuclide Therapy Project Summary In this competing renewal application, our overall objective remains as previously described - to enable a patient- specific treatment planning approach to delivering radiopharmaceutical therapy (RPT) by establishing methodologies and developing computational tools that better predict tissue toxicity and tumor response. In the prior grant period we addressed RPT with beta-emitters and established a methodology to plan combination external beam radiotherapy with beta-emitter RPT. In this renewal application we propose to address the dosimetry of alpha-particle emitters. α-particle emitters have been recognized as highly potent therapeutics that are fundamentally novel in their mechanism and largely impervious to resistance. The recent FDA approval of one such agent has led to numerous efforts to bring more alpha-emitter RPTs (αRPT) to the clinic. α-particles are short-range (50 to 100 µm,) high linear energy transfer (LET) particles which cause preponderant double- stranded break damage to DNA. Although there is a well-established dosimetry formalism for risk evaluation of these, there is no dosimetry formalism able to account for the high LET and the short range of these to evaluate toxicity and efficacy – therapeutic endpoints. We propose to develop a methodology that accounts for the short range and high potency of these agents. The specific aims to do this are: 1. Measure the Relative Biological Effectiveness (RBE) of normal tissue for α-particle emitter radiopharmaceuticals (αRPTs). No systematic evaluation of RBE for normal tissues has been undertaken. Currently available values are largely derived from in vitro cell studies. Since biological effect = Absorbed Dose (AD) x RBE, normal tissue RBE is needed to avoid toxicity, plan therapy, and safely execute phase I AD escalation trials for αRPT.2. Measure tumor RBE, in vivo for 3 tumor types, compare to RBE, in vitro. Tumor RBE is needed to assess efficacy as well as for treatment optimization to avoid over-treating patients.3. Develop and incorporate macro to micro modeling for α- particle emitter dosimetry into 3D-RD. The macro to micro approach developed with prior support has been implemented for kidney dosimetry of intact antibodies, labeled with different alpha-emitters. This aim will extend this work to peptides and small molecules and incorporate the method into the 3D-RD platform to establish a new version of 3D-RD (α3D-RD).4. Establish models that enable combined external beam RT (XRT) with αRPT. There is a strong rationale for combining XRT with αRPT. Such treatment has not been implemented because a methodology that incorporates micro-scale RBE-weighted dose distribution in dose maps and dose- volume histograms that can be used in XRT planning software does not exist. We will build upon the XRT-RPT method that we developed previously and that is currently being used with Sm-153, (a beta-particle emitter) in an ongoing clinical trial at Hopkins in patients with osteosarcoma to establish a formalism that can be incorporated into α3D-RD. Successful completion of these aims will enable a dosimetry-driven, treatment planning approach to implementing this novel and highly potent therapeutic modality.

放射线治疗中的剂量反应 项目摘要 在此竞争性更新应用中，我们的总体目标仍然如前所述 - 使患者能够 通过建立提供放射药物治疗（RPT）的特定治疗计划方法 方法和开发计算工具可以更好地预测组织毒性和肿瘤反应。在 以前的赠款期，我们用β发行器向RPT讲话，并建立了一种计划组合的方法 外束放疗与β射手RPT。在此续订应用程序中，我们建议解决 α粒子发射剂的剂量法。 α粒子发射器已被认为是高潜在的治疗 从根本上是新颖的机制，在很大程度上不受抵抗的影响。最近的FDA批准 这样的代理人导致了许多努力，将更多的α发射极RPT（αRPT）带到诊所。 α粒子 是短距离（50至100 µm）高线性能传递（LET）颗粒 滞留对DNA的断裂破坏。尽管有一个良好的剂量法，以评估风险 这些，没有能够说明剂量的剂量，可以说明这些格式的高度和短范围来评估 毒性和效率 - 治疗终点。我们建议开发一种说明简短的方法 这些试剂的范围和高效力。执行此操作的具体目的是：1。测量相对生物学 α粒子发射器放射性药物（αRpts）的正常组织的有效性（RBE）。没有系统 已经进行了正常组织的RBE评估。当前可用的值主要来自 体外细胞研究。由于生物效应=吸收剂量（AD）X RBE，因此需要正常的组织RBE以避免 毒性，计划治疗和安全执行I阶段AD升级试验的αRPT.2。测量肿瘤RBE，体内 对于3种肿瘤类型，与RBE相比，体外。需要肿瘤RBE来评估效率和治疗 优化以避免过度治疗患者3。开发并结合了α-微型建模 粒子发射器剂量测定成3D-RD。在先前支持的情况下开发的微观方法是 用于完整抗体的肾脏剂量法，并用不同的α发射体标记。这个目标将扩展 这项工作用于抚摸和小分子，并将该方法纳入3D-RD平台以建立一个 3D-RD（α3D-RD）的新版本.4。建立模型，使外部光束RT（XRT）与 αrpt。将XRT与αRPT结合在一起有很强的理由。这种治疗尚未实施 因为一种在剂量图和剂量中纳入微尺度RBE加权剂量分布的方法 可以在XRT计划软件中使用的音量直方图。我们将建立在XRT-RPT上 我们以前开发的方法，目前正在SM-153（beta粒子发射极）中使用。 在霍普金斯（Hopkins 掺入α3D-RD中。这些目标的成功完成将实现剂量驱动的治疗 计划实施这种新颖且高度潜在的治疗方式的方法。