# Alterations in DNA Damage following Major Surgery and Hyperthermic Intraperitoneal Chemotherapy

> **NIH NIH R03** · UNIVERSITY OF KENTUCKY · 2022 · $76,339

## Abstract

ABSTRACT/SUMMARY
Nearly 10% of patients with metastatic colorectal cancer (mCRC) have progression of disease involving the
spread of metastatic cancer to the peritoneal cavity. These patients generally have the worst outcomes for all
patients with mCRC. A recent phase III multicenter clinical trial has shown that single-agent immune checkpoint
inhibitor (ICI) has greater efficacy and better safety profile than standard cytotoxic chemotherapy regimens for
patients with mCRC. Importantly, indications to receive ICI therapy are dependent on the measurement of high
tumor mutation burden (TMB), neoantigen burden, and microsatellite instability (MSI) status. These direct and
indirect measures of genomic instability predict clinical response to ICIs, however, only 5% of patients are
currently eligible to receive these therapies.
Patients with mCRC with peritoneal spread of disease may undergo major cytoreductive surgery (CRS), during
which all gross sites of disease are resected. CRS is combined with heated intraperitoneal chemotherapy
(HIPEC) with mitomycin C at 43°C to eradicate microscopic disease. We hypothesize that major surgical
inflammation from CRS and the heat and chemotherapy of HIPEC altogether increase genomic instability.
Surgical inflammation is known to activate heat shock proteins (Hsps) which may destabilize its regulatory control
over mismatch repair (MMR) proteins leading to deficient DNA repair. This condition combined with the DNA
damaging effects of mitomycin c and heat may lead to high TMB, increased neoantigens, and altered MSI in
occult microscopic mCRC cells. Our overarching hypothesis is that patients undergoing CRS/HIPEC will be
eligible to receive and will benefit from ICI therapy.
We propose to obtain blood samples and surgical tissues before and after CRS/HIPEC from patients with mCRC.
These specimens will be assessed for changes in TMB and neoantigens (Aim 1) and MMR/MSI (Aim 2). From
the surgical tissues, we will also create paired patient-derived organoids (PDOs) from which we will investigate
Hsps, MMR proteins, and MSI. Our prior studies using PDOs from CRS/HIPEC patients support their use to
assess sensitivities to ICI therapies before and after CRS/HIPEC. We propose the following specific aims:
Specific Aim 1. To measure alterations in TMB and neoantigens as a result of the heat and DNA damaging
effects of mitomycin C in mCRC patients undergoing CRS/HIPEC.
Specific Aim 2. To determine whether surgical inflammation combined with heat and DNA damaging effects of
mitomycin C from CRS/HIPEC disrupt Hsp-stabilization of MMR proteins to increase MSI.

## Key facts

- **NIH application ID:** 10509828
- **Project number:** 1R03CA267326-01A1
- **Recipient organization:** UNIVERSITY OF KENTUCKY
- **Principal Investigator:** JOSEPH KIM
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $76,339
- **Award type:** 1
- **Project period:** 2022-08-05 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10509828

## Citation

> US National Institutes of Health, RePORTER application 10509828, Alterations in DNA Damage following Major Surgery and Hyperthermic Intraperitoneal Chemotherapy (1R03CA267326-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10509828. Licensed CC0.

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