Project 1: FLASH vs. Standard radiotherapy for treatment of PDAC and sparing normal intestine tissues

项目 1：FLASH 与标准放疗治疗 PDAC 并保护正常肠道组织

基本信息

批准号：
10573280
负责人：
Constantinos Koumenis
金额：
$ 41.4万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-15 至 2027-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10573280
关键词：
Acute Allografting Blood Cells Blood Vessels Canis familiaris Carbon Cell Proliferation Cells Characteristics Clinical Management Clinical Trials Columnar Cell Coupled Data Development Diagnosis Disease Dose Dose Rate Endothelial Cells Endothelium Epithelial Cells Epithelium Exhibits Fibrosis Fractionation Gene Expression Gene Expression Profile Gene Expression Profiling Genetic Genetic Determinism Genetically Engineered Mouse Growth Immune Immune response Immunotherapy Induction of Apoptosis Inflammatory Response Injury Interferon Type II Intestines Knock-out Knockout Mice LGR5 gene Link Liver Lung Malignant Neoplasms Malignant neoplasm of pancreas Mediating Modality Modeling Molecular Mus Normal tissue morphology Organ Pancreatic Adenocarcinoma Play Protons Publishing Radiation Tolerance Radiation therapy Resectable Role Sampling Scanning Scheme Signal Transduction Skin Small Intestines Survival Rate TP53 gene Testing Text Therapeutic Time Tissues Toxic effect Unresectable antitumor effect base beta catenin biophysical properties cadherin 5 carcinogenesis epithelial stem cell experimental study gastrointestinal gastrointestinal epithelium improved intestinal crypt intestinal epithelium mouse model novel pancreatic neoplasm particle progenitor proton therapy response sarcoma senescence single-cell RNA sequencing stem cell population stem cell proliferation stem cells translational study tumor tumor growth tumorigenesis villin

项目摘要

SUMMARY (changes from previous submission denoted with shaded text ) Project 1 will test the overall hypothesis that Proton Radiotherapy delivered in ultra-fast dose rates (>60 Gy/sec), termed FLASH-PRT, controls Pancreatic tumor growth equally well as Standard dose rate (<1 Gy/sec) Proton Radiotherapy (S-PRT), while sparing normal intestinal tissue from acute and delayed toxicity. Successful completion of the proposed studies will lead to better mechanistic understanding of the differential effects of F-PRT compared to S-PRT at the molecular, genetic and organismic level and will define the parameters necessary for the initiation of clinical trials. In preliminary published studies, we demonstrated that compared to S-PRT, F-PRT increases overall survival of model mouse models and also ameliorates late stage toxicity, primarily fibrosis. At the same time, F-PRT was shown to be equipotent to S-PRT in controlling the growth of allografted syngeneic tumors. Studies using single-cell RNA- sequencing (scRNAseq), reveal intriguing differences in gene expression profiles in the response of epithelial stem/progenitor cells to F-PRT compared to S-PRT which coincide with a reduction in the inhibitory effect on progenitor cell proliferation. In Aim 1, we will define the dosimetric and biophysical parameters which deliver maximum normal tissue sparing and anti-tumor effect of F-PRT using syngeneic flank and orthotopic models and Genetically Engineered Mouse model (GEMM) of PanCa. We will then link perform a dose-escalation study using these optimized parameters and focal RT to determine in F-PRT improves overall survival compared to S-PRT . In Aim 2, we will delineate the mechanism of differential response of normal intestinal and liver tissues including epithelium, vascular, immune and circulating cells to S-PRT and F-PRT, using scRNAseq to deconvolute the differential patterns of gene expression elicited by the two modalities. In Aim 3, we will use GEMM with tissue-specific deletion of p53 (epithelium vs. endothelium) to investigate the role of epithelial and endothelial cells respectively, in the response to S-PRT and F-PRT on acute and late toxicity coupled with reduced epithelial barrier loss. We will also test the involvement of the Wnt/β-catenin and R-Spondin signaling in mediating F- PRT sparing of normal intestinal epithelium . This project will benefit from, and contribute to, conceptual advances in the other projects. Information garnered from scRNA-seq will inform experiments on skin toxicity and progenitor cell fate in Project 2, including the canine trial on sarcoma. Results from epithelial-specific and endothelial-specific p53 knockout mice in this project will guide experiments in Projects 2 and Project 3 in sarcoma and lung. Project 3 will generate Carbon and Proton-irradiated intestinal and PanCa samples which will be analyzed by Project 1. Finally, Project 4 will develop a pencil-beam scanning approach which we will employ in the dose-escalation experiments under Aim 1.

摘要（与之前提交的更改标记为阴影文本）项目 1 将测试质子放射治疗以超快剂量率（> 60 Gy/sec），称为 FLASH-PRT，与标准剂量率（<1 戈瑞/秒）质子放射治疗（S-PRT），同时使正常肠道组织免受急性和迟发毒性的影响。成功完成拟议的研究将有助于更好地理解差异的机制 F-PRT 与 S-PRT 在分子、遗传和有机体水平上的影响相比较，并将定义在初步发表的研究中，我们证明了启动临床试验所需的参数。与 S-PRT 相比，F-PRT 提高了模型小鼠模型的总体存活率，并改善了晚期阶段毒性，主要是纤维化，同时，F-PRT 在控制纤维化方面与 S-PRT 等效。使用单细胞 RNA 测序 (scRNAseq) 的研究揭示了同种异体移植同基因肿瘤的生长。上皮干细胞/祖细胞对 F-PRT 反应中基因表达谱的有趣差异与 S-PRT 相比，这同时降低了对祖细胞增殖的抑制作用。目标 1，我们将定义剂量测定和生物物理参数，以最大程度地保护正常组织使用同源侧翼和原位模型以及基因工程研究 F-PRT 的抗肿瘤作用 PanCa 的小鼠模型（GEMM）然后我们将链接执行。使用这些优化的剂量递增研究与 S-PRT 相比，F-PRT 中确定的参数和局部 RT 可提高总体生存率 .在目标 2 中，我们将描绘正常肠和肝组织（包括上皮）的差异反应机制，血管、免疫和循环将细胞转为 S-PRT 和 F-PRT，使用 scRNAseq 对差异进行解卷积在目标 3 中，我们将使用具有组织特异性的 GEMM。删除 p53（上皮细胞与内皮细胞）以研究上皮细胞和内皮细胞的作用分别针对 S-PRT 和 F-PRT 对急性和晚期毒性的反应以及上皮细胞减少屏障损失。我们还将测试 Wnt/β-catenin 和 R-Spondin 信号传导在介导 F- PRT 保留正常肠上皮该项目将受益于概念性，并为此做出贡献。从 scRNA-seq 收集的信息将为皮肤毒性实验提供信息。和项目 2 中的祖细胞命运，包括上皮特异性和肉瘤的犬试验结果。该项目中的内皮特异性 p53 敲除小鼠将指导项目 2 和项目 3 的实验项目 3 将产生碳和质子辐照的肠道和 PanCa 样本。将通过项目 1 进行分析。最后，项目 4 将开发一种笔形束扫描方法，我们将使用该方法用于目标 1 下的剂量递增实验。