权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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：
10333798
负责人：
Constantinos Koumenis
金额：
$ 48.11万
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/10333798
关键词：
Acute Apoptosis 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 Epithelial Cells Exhibits Fibrosis Fractionation Gene Expression Gene Expression Profile Genetic Determinism Genetically Engineered Mouse Growth Immune Immune response Immunotherapy 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 Molecular Genetics Mus Normal tissue morphology Organ Organism 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 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 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(与之前提交的内容相比有变化