Dose-Response in Radionuclide Therapy

放射性核素治疗的剂量反应 项目摘要 在这一竞争性续期申请中，我们的总体目标仍如前所述-使患者- 通过建立放射性药物治疗（RPT）的特定治疗计划方法 方法和开发计算工具，更好地预测组织毒性和肿瘤反应。在 在前一个资助期，我们用β-发射体解决了RPT问题，并建立了一种计划组合的方法 使用β-发射器RPT的外部射束放射治疗。在此更新申请中，我们建议解决 α粒子发射体的剂量测定。α粒子发射体已被认为是高效的治疗剂， 其机制基本上是新颖的，并且很大程度上不受耐药性的影响。最近FDA批准 一种这样的药剂已经导致了大量的努力，以将更多的α-发射体RPT（αRPT）带到临床。α粒子 是短程（50至100 µm）高线性能量转移（LET）粒子，可导致主要的双- DNA链断裂损伤。虽然有一个完善的剂量学形式主义的风险评价， 对于这些，没有剂量学形式能够解释高LET和这些的短范围以进行评估 毒性和疗效-治疗终点。我们建议制定一种方法， 范围和这些代理商的高效力。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（α RPT）的有效性（RBE）。没有系统 已经对正常组织的RBE进行了评估。目前可用的值主要来自于 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以避免 毒性，计划治疗，并安全地执行α RPT的I期AD递增试验。测量体内肿瘤RBE 对于3种肿瘤类型，与RBE相比，在体外。需要肿瘤RBE来评估疗效和治疗 优化以避免过度治疗患者。开发并将宏观模型与微观模型相结合， 粒子发射器剂量测定到3D-RD中。在之前的支持下开发的宏观到微观方法已经 实施用于用不同α-发射体标记的完整抗体的肾脏剂量测定。这一目标将扩大 这项工作针对肽和小分子，并将该方法纳入3D-RD平台以建立 新版本的3D-RD（α3D-RD）。4.建立模型，使组合外束RT（XRT）与 αRPT。XRT与αRPT联合使用有很强的理由。这样的待遇一直没有落实 因为在剂量图和剂量分布图中结合微尺度RBE加权剂量分布的方法， 不存在可用于XRT计划软件的体积直方图。我们将以XRT-RPT为基础， 我们以前开发的方法，目前正在使用Sm-153（β粒子发射器）， 霍普金斯正在进行的一项骨肉瘤患者的临床试验， 纳入α3D-RD。这些目标的成功完成将使一个剂量驱动的， 规划的方法来实施这种新的和高度有效的治疗方式。

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.