Radiobioeffect Modeling of αRPT

如果吸收剂量用于基于α粒子发射器的放射药物治疗计划 (DNARPT)，α双链断裂修复状态的影响--最有可能影响反应的过程 -必须加以考虑，以便可靠地预测毒性和疗效。项目1至3的重点是 估算αRPT的组织吸收剂量。在项目4中，我们采用这些吸收剂量估计值并检查 临床上可实施的评估DNA DSB修复(DSBR)状态的方法是否会改善 接受α快速放射治疗的患者的吸收剂量与反应关系。我们的总体假设是组织 用DNADSB修复的定量指标调整吸收剂量能更好地预测α治疗反应 通路功能。为了验证这一假设，我们引入了一种新的方法来评估修复途径 功能，并将其与临床前和临床方案相结合，使我们能够严格评估影响 说明DSBR功能与吸收剂量和反应之间的关系。我们将使用前列腺癌(PCA) 作为拟议研究的模型系统。前列腺癌患者已经用223RaCl2(Xofigo)治疗， 美国食品和药物管理局批准的αRPT。也有证据表明，这种治疗的疗效受到躯体和/或 DNADSB修复中的种系缺陷。因此，拟议的研究将在一个背景下检验我们的假设 这在临床上是直接相关的。 目的1：利用PCa细胞系及其修复缺陷等基因变异体，研究DNADSB与吸收剂量的关系 在BRCA2-/-和ATM-/-相关DNA DSB修复缺陷的背景下，体外损伤和修复；自 反应受细胞间相互作用的影响，在(A)单层和(B)球状培养中进行这些研究。 目标2：收集体内剂量与DSBR数据，类似于目标1收集的数据。在(A)中进行这些研究 携带目标1和(B)中使用的细胞系及其同基因变体的异种移植的小鼠延长了正常 (A)利用猪骨髓和肾组织进行器官研究--AIM 3项目中的剂量与毒性研究 3.(C)在接受223Ra治疗的PCa患者中，使用正常组织和肿瘤D估计，以及DSBR估计 评估DSBR缺陷对DVS肿瘤和正常组织反应的影响。DSBR 缺陷将使用从液体中获得的DNA DSB修复(DDR)途径突变状态进行评估 活组织检查。 目的3：建立可用于优化DSBR选择和给药方案的数学模型 抑制剂(DSBRi)，并识别其基因组/转录图谱和剂量学将使其 对αRPT±DSBRi治疗的应答率可能高或低。 通过将αRPT剂量测量与DSBR功能相结合，本项目中提出的工作完成了 图1中描述的过渡，同时还提供和验证了一种新的技术，该技术可以 应用于研究DSBR抑制剂在肿瘤α快速反应中的作用。

If absorbed dose is to be used in treatment-planning based α-particle emitter radiopharmaceutical therapy (αRPT), the impact of DNA double-strand break (DSB) repair status- the process most likely to affect response - must be considered in order to reliably predict toxicity and efficacy. Projects 1 through 3 have focused on estimating tissue absorbed doses for αRPT. In project 4, we take these absorbed dose estimates and examine whether clinically implementable methods for evaluating DNA DSB repair (DSBR) status will improve the absorbed dose vs response relationship for patients undergoing αRPT. Our overall hypothesis is that tissue absorbed dose will better predict αRPT response when adjusted by quantitative measures of DNA DSB repair pathway functionality. To test this hypothesis, we introduce a novel approach to assessing repair pathway functionality and couple it with preclinical and clinical scenarios that will allow us to rigorously evaluate the impact of accounting for DSBR functionality in relating absorbed dose to response. We will use prostate cancer (PCa) as a model system for the proposed studies. Prostate cancer patients are already treated with 223RaCl2 (Xofigo), an FDA approved, αRPT. There is also evidence that the efficacy of this treatment is impacted by somatic and/or germline deficiencies in DNA DSB repair. Accordingly, the proposed studies, will test our hypothesis in a context that is immediately clinically relevant. Aim 1: Using PCa cell lines and their repair deficient isogenic variants, relate absorbed dose (D) to DNA DSB damage and repair, in vitro, in the context of BRCA2-/- and ATM-/- -related DNA DSB repair deficiencies; since response is impacted by cell-cell interactions, perform these studies in (a) monolayer and (b) spheroid culture. Aim 2: Collect dose- vs DSBR data, in vivo, analogous to that collected in Aim 1. Perform these studies in (a) mice bearing xenografts of the cell lines and their isogenic variants used in Aim 1 and (b) extend the normal organ studies of (a) using porcine marrow and kidney tissues from the dose vs toxicity studies of Aim 3 in Project 3. (c) In PCa patients treated with 223Ra, use normal tissue and tumor D estimates, with estimates of DSBR functionality to assess the impact of DSBR deficiencies on D vs tumor and normal tissue response. DSBR deficiencies will be assessed using DNA DSB repair (DDR) pathway mutation status obtained from liquid biopsies. Aim 3: Develop a mathematical model that may be used to optimize the selection and dosing schedule of DSBR inhibitors (DSBRi) and identify patients whose genomic/transcriptomic profile and dosimetry would make them likely high or low responders to αRPT±DSBRi therapy. By coupling αRPT dosimetry with the DSBR functionality, the work proposed in this project completes the transition depicted in figure 1 of the overview while also providing and validating a novel technique that can be applied to investigating the role of DSBR inhibitors in αRPT of cancer.