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

> **NIH NIH P01** · UNIVERSITY OF PENNSYLVANIA · 2022 · $481,131

## Abstract

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-esca...

## Key facts

- **NIH application ID:** 10333798
- **Project number:** 1P01CA257904-01A1
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Constantinos Koumenis
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $481,131
- **Award type:** 1
- **Project period:** 2022-02-15 → 2027-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10333798

## Citation

> US National Institutes of Health, RePORTER application 10333798, Project 1: FLASH vs. Standard radiotherapy for treatment of PDAC and sparing normal intestine tissues (1P01CA257904-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10333798. Licensed CC0.

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