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.

放射性核素治疗的剂量反应 项目概要 在这个竞争性更新应用程序中，我们的总体目标仍然如前所述 - 使患者能够 通过建立特定的治疗计划方法来提供放射性药物治疗（RPT） 方法论和开发计算工具，以更好地预测组织毒性和肿瘤反应。在 在之前的拨款期间，我们利用 beta 发射器解决了 RPT 问题，并建立了一种计划组合的方法 使用 β 发射体 RPT 进行外照射放射治疗。在此续签申请中，我们建议解决 α粒子发射器的剂量测定。 α-粒子发射器已被认为是高效的治疗方法 它们的机制从根本上来说是新颖的，并且基本上不受阻力影响。最近FDA批准了 一种这样的药物导致了无数的努力，将更多的α发射体RPT（αRPT）引入临床。 α粒子 是短程（50 至 100 µm）高线性能量转移 (LET) 粒子，会导致主要的双 DNA 链断裂损伤。尽管有一个完善的剂量测定形式来进行风险评估 这些，没有剂量测定形式能够解释高 LET 和这些的短范围来评估 毒性和功效——治疗终点。我们建议开发一种方法来解决短期问题 这些药剂的范围和高效力。这样做的具体目标是： 1. 测量相对生物学 正常组织对 α 粒子发射体放射性药物 (αRPT) 的有效性 (RBE)。没有系统性 已经对正常组织的 RBE 进行了评估。目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，因此需要正常组织 RBE 来避免 毒性、计划治疗并安全地执行 αRPT.2 的 I 期 AD 升级试验。体内测量肿瘤 RBE 对于 3 种肿瘤类型，与 RBE 进行体外比较。需要肿瘤 RBE 来评估疗效和治疗 优化以避免过度治疗患者。3．开发并整合 α- 的宏观到微观模型 将粒子发射器剂量测定转化为 3D-RD。在先前的支持下开发的从宏观到微观的方法已经 用于用不同的α发射体标记的完整抗体的肾脏剂量测定。这一目标将延伸 这项工作适用于肽和小分子，并将该方法整合到 3D-RD 平台中，建立一个 新版本3D-RD（α3D-RD）.4。建立模型，使组合外束 RT (XRT) 与 αRPT。将 XRT 与 αRPT 结合起来有充分的理由。此类处理尚未实施 因为一种方法将微尺度 RBE 加权剂量分布纳入剂量图和剂量- 不存在可在 XRT 规划软件中使用的体积直方图。我们将以 XRT-RPT 为基础 我们之前开发的方法，目前正在与 Sm-153（一种 β 粒子发射器）一起使用 霍普金斯大学正在进行一项针对骨肉瘤患者的临床试验，旨在建立一种可以 纳入α3D-RD。成功完成这些目标将使剂量测定驱动的治疗成为可能 实施这种新颖且高效的治疗方式的规划方法。