Radiobioeffect Modeling of αRPT

αRPT 的放射生物效应建模

• 批准号: 10713713
• 负责人: George Sgouros
• 金额: $ 44.59万
• 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/10713713
• 关键词: Accounting; Affect; Alpha Particle Emitter; BRCA2 gene; Beta Cell; Beta Particle; Biological; Biological Models; Bone Marrow; Cancer Patient; Cell Communication; Cell Line; Cell Proliferation; Cells; Clinical; Clinical Trials; Combined Modality Therapy; Complement; Coupling; DNA; DNA Damage; DNA Double Strand Break; DNA Repair; DNA Repair Gene; Data; Dependence; Disease; Dose; Double Strand Break Repair; Evaluation; Exposure to; FDA approved; FOLH1 gene; Family suidae; Genomics; Growth; Hematopoietic; Human; Image; In Vitro; Kidney; Leukocytes; Malignant neoplasm of prostate; Marrow; Measurement; Measures; Metastatic Neoplasm to the Bone; Methods; Modeling; Molecular; Mus; Mutation; Normal tissue morphology; Organ; Pathway interactions; Patients; Peripheral; Photons; Process; Property; Proteomics; Radiation Tolerance; Radiobiology; Radiopharmaceuticals; Radium; Role; Sampling; Schedule; Small Intestines; Techniques; Testing; Time; Tissues; Toxic effect; Treatment Efficacy; Treatment-related toxicity; Tumor Tissue; Variant; Work; Xenograft procedure; absorption; advanced prostate cancer; anti-PSMA; bone; cancer therapy; cell killing; clinically relevant; dosimetry; genomic profiles; homologous recombination; improved; in vivo; inhibitor; inhibitor therapy; liquid biopsy; mathematical model; monolayer; mutational status; novel; novel strategies; patient response; pre-clinical; predicting response; prostate cancer cell; prostate cancer cell line; radiation effect; repaired; response; simulation; small molecule; transcriptomics; treatment planning; treatment response; tumor; tumor growth; tumor xenograft

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.

如果吸收剂量用于基于治疗计划的α粒子发射器放射性药物治疗 （αRPT），DNA双链断裂（DSB）修复状态的影响-最有可能影响反应的过程 - 为了可靠地预测毒性和有效性，必须考虑。项目1至3的重点是 估计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， 评估DNA DSB修复（DSBR）状态的临床可实施方法是否会改善 接受αRPT的患者的吸收剂量与反应关系。我们的总体假设是 当通过DNA DSB修复的定量测量进行调整时，吸收剂量将更好地预测αRPT反应 路径功能。为了验证这一假设，我们介绍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在将吸收剂量与反应联系起来方面的功能。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223 RaCl 2（Xofigo）治疗， FDA批准的αRPT。还有证据表明，这种治疗的疗效受到躯体和/或神经系统疾病的影响。 DNA DSB修复的生殖系缺陷。因此，拟议的研究将在一个背景下测试我们的假设， 与临床有直接关系 目的1：使用PCa细胞系及其修复缺陷同基因变体，将吸收剂量（D）与DNA DSB联系起来 损伤和修复，在体外，在BRCA 2-/-和ATM-/-相关的DNA DSB修复缺陷的背景下; 响应受细胞-细胞相互作用的影响，在（a）单层和（B）球状体培养物中进行这些研究。 目的2：收集体内剂量与DSBR数据，类似于目的1中收集的数据。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物的小鼠延长了正常的 器官研究：（a）使用来自项目目标3剂量与毒性研究的猪骨髓和肾组织 3. (c)在接受223 Ra治疗的PCa患者中，使用正常组织和肿瘤D估计值，以及DSBR估计值 评估DSBR缺陷对D与肿瘤和正常组织反应的影响的功能。DSBR 将使用从液体中获得的DNA DSB修复（DDR）途径突变状态来评估缺陷。 活组织检查 目的3：建立一个数学模型，可用于优化DSBR的选择和投加时间表 抑制剂（DSBRi），并确定患者的基因组/转录谱和剂量测定将使他们 αRPT±DSBRi治疗的可能高或低应答者。 通过将αRPT剂量测定与DSBR功能相结合，本项目中提出的工作完成了 同时还提供并验证了一种新颖的技术， 应用于研究DSBR抑制剂在肿瘤αRPT中的作用。