# Tumor-selective inhibition of DNA repair using pHLIP

> **NIH NIH F30** · YALE UNIVERSITY · 2020 · $46,300

## Abstract

PROJECT SUMMARY
The development of therapeutic agents that specifically target cancer cells while sparing healthy tissue would
represent an important advance in cancer therapy by reducing toxicity to healthy tissue. Acidity is a hallmark
of the tumor microenvironment that can be targeted using pH-low insertion peptides (pHLIPs). Cargo attached
to pHLIP can be selectively delivered to tumor cells in vivo based on the acidity of the tumor microenvironment.
The objective of this proposal is to develop a tool to inhibit DNA repair specifically within the tumor
microenvironment while sparing normal tissue, with a long-term goal of developing novel cancer treatments
with wider therapeutic indices. DNA repair is crucial for tumor cell survival after exposure to ionizing radiation
(IR), and thus inhibiting DNA repair causes increased cell death after IR exposure (radiosensitization).
Furthermore, in susceptible genetic backgrounds, inhibition of DNA repair causes cell death in the absence of
radiation through a mechanism known as synthetic lethality. Small molecule inhibitors of non-homologous end
joining (NHEJ), a critically important pathway in DNA repair, cause exquisite radiosensitization. However, the
clinical use of these inhibitors has been hindered by in vivo toxicity and poor bioavailability. This proposal aims
to use new technologies to overcome the current limitations in targeting NHEJ by developing peptide nucleic
acid (PNA) based oligomers to reduce expression of the essential NHEJ factor Ku80 and using pHLIPs to
selectively deliver these PNA molecules to tumors (pHLIP-αKu80(γ)), with the hypothesis that this approach
will allow for the selective radiosensitization of tumor cells. This hypothesis will be tested through the following
aims. To evaluate the activity of pHLIP-αKu80(γ) against cancer cells in culture (Aim 1), pHLIP-conjugated
PNAs with antisense activity against Ku80 will be tested for pH-dependent activity against cancer cells in
culture. Specifically, effects on DNA repair and cell survival after IR will be determined. Efforts will also be
made to identify genetic backgrounds that demonstrate synthetic lethality with pHLIP-αKu80(γ) treatment. To
evaluate and optimize the tumor radiosensitizing effects of pHLIP-αKu80(γ) in vivo (Aim 2), the pharmacology
and toxicity of pHLIP-αKu80(γ) treatment will be assessed, and tumor growth delay and clonogenic survival
assays will be used to measure radiosensitization and synthetic lethal interactions. The development of
pHLIP-αKu80(γ) would provide a means of selectively radiosensitizing tumors cells regardless of tumor type,
biomarker expression, and genetic background. By inhibiting DNA repair selectively in tumors, this approach
spares healthy tissue and is thus expected to reduce toxicity. Therefore, pHLIP-αKu80(γ) could be used to
improve the efficacy of radiation therapy without causing additional toxicity, marking an important clinical
advancement.
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## Key facts

- **NIH application ID:** 9977999
- **Project number:** 5F30CA221065-03
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Alanna Kaplan
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $46,300
- **Award type:** 5
- **Project period:** 2018-08-01 → 2021-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9977999

## Citation

> US National Institutes of Health, RePORTER application 9977999, Tumor-selective inhibition of DNA repair using pHLIP (5F30CA221065-03). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9977999. Licensed CC0.

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