# Project 3: Enhanced Sensitivity of Tumors to Proton Beam Therapy: Mechanisms and Biomarkers.

> **NIH NIH P01** · MASSACHUSETTS GENERAL HOSPITAL · 2022 · $601,652

## Abstract

Project 3 - SUMMARY
While proton beam therapy (PBT) has superior physical characteristics compared to standard photon
radiation, its biological properties have been thought to be similar to photons. This is reflected in the use of a
generic relative biological effectiveness (RBE) of 1.1 to scale the physical dose delivered for both cancer
and normal tissues. However, pre-clinical data from our groups and others are emerging to indicate that the
RBE of PBT varies and may be dependent on intrinsic tumor cell biology. Such RBE variations are likely
genomically defined and exist across individual tumors of a given cancer type. This is a vastly understudied
area with potential for substantial clinical impact as we are advancing our ability to genomically profile
cancers to identify candidate predictive biomarkers. Thus, our overall objective is to establish distinct
biological properties of PBT relative to photon radiation and determine if these differential properties result in
variable RBE values across genomically diverse tumors. By combining synergistic MGH and MDACC
expertise, we will integrate advanced physical computation techniques with novel biological tools, such as
nucleosome-resolution genomic mapping of DNA double-strand breaks, to study the hypothesized unique
biological damage produced by protons. We will conduct the following Specific Aims: (1) Simulate DNA
damage induction and repair for proton vs photon irradiation; (2) Experimentally elucidate targetable
differences in the induction and removal of DNA breaks following proton vs photon irradiation; (3) Identify
candidate genomic biomarkers that predict increased proton RBE in annotated cancer cell lines; (4) Validate
biomarker-correlated proton sensitivity in clinically relevant tumor models and in patients. These studies will
leverage extensive pre-clinical tumor model collections as well as clinical trial specimens at both institutions.
The knowledge gained will quickly influence the treatment of cancer patients through the introduction of
novel clinical trials with stratification based on genomic biomarkers that predict sensitivity to PBT.

## Key facts

- **NIH application ID:** 10491858
- **Project number:** 5P01CA261669-02
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** DAVID R GROSSHANS
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $601,652
- **Award type:** 5
- **Project period:** 2021-09-21 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10491858

## Citation

> US National Institutes of Health, RePORTER application 10491858, Project 3: Enhanced Sensitivity of Tumors to Proton Beam Therapy: Mechanisms and Biomarkers. (5P01CA261669-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10491858. Licensed CC0.

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