# Nanotechnology for targeted therapy and fundamental understanding oftherapeutic resistance in triple negative breast cancer

> **NIH NIH R01** · UNIV OF MARYLAND, COLLEGE PARK · 2024 · $235,233

## Abstract

Project Summary/Abstract
 Breast cancer is the second leading cause of cancer-related deaths of American women. In particular, no
targeted therapy is clinically available for nearly all triple negative breast cancer (TNBC). Cancer arises as a
result of accumulating genetic alterations. Therefore, developing novel strategies to precisely target the genetic
alterations of TNBC may be valuable for combating the malignant disease. TP53 is a pivotal tumor suppressor
gene inactivated by mutation or deletion in most human cancers. Tremendous effort has been made to restore
the activity of the p53 protein encoded by TP53 for cancer treatment. Unfortunately, no p53-based therapy has
been successfully translated into the clinic, due to the complexity of p53 signaling. Therefore, identifying
vulnerabilities conferred by TP53 deletion instead of restoring the p53 activity is a novel strategy for combating
cancer. In our recent work published in Nature and Nature Nanotechnology, we revealed genomic deletion of
TP53 is often accompanied by hemizygous (i.e., partial) loss of a neighboring gene POLR2A essential for cell
survival, and virtually all 53% TNBCs with TP53 deletion harbor hemizygous POLR2A loss (TP53/POLR2Aloss).
 Our preliminary data show that suppressing POLR2A expression by RNA interference with small interfering
RNA (siRNA) delivered using a low pH-activated nanobomb selectively inhibits the proliferation, survival, and
tumorigenic potential of TP53/POLR2Aloss TNBC cells. The nanobomb protects the siRNA in blood and enables
endo/lysosomal escape of the siRNA into the cytosol where the siRNA performs its POLR2A inhibition function
after cell uptake. Moreover, the nanobomb-mediated delivery of POLR2A-targeting siRNA selectively inhibits
the growth of orthotopic TP53/POLR2Aloss TNBC tumors, with no evident systemic toxicity demonstrated by the
data on animal body weight and blood proteins (for liver function) and cytokines (for immune responses).
 However, a small fraction of breast cancer cells overexpressed with the variant CD44 (note: not the non-
variant or normal CD44 on normal stem cells) have been shown to be particularly resistant to clinically used
chemotherapy drugs of TNBC such as paclitaxel (PTX). Since POLR2A is indispensable for cancer cells to
survive, we hypothesize that targeted co-delivery of the POLR2A-targeting siRNA and PTX to the variant
CD44+ cancer cells can overcome the TNBC drug resistance. We will further develop the aforementioned low
pH-activated nanobomb that has no active targeting, to be capable of actively targeting both the variant CD44+
cells and tumor vasculature. Since cancer metastasis is the major cause of cancer-related death, we will test
the hypothesis using not only the aforementioned orthotopic/primary TNBC tumors but also metastatic TNBC
model. Furthermore, we will investigate the mechanisms of resistance to the POLR2A-targeted therapy using
not only 2D and xenograft but also 3D TNBC models generated using...

## Key facts

- **NIH application ID:** 10814962
- **Project number:** 5R01CA243023-05
- **Recipient organization:** UNIV OF MARYLAND, COLLEGE PARK
- **Principal Investigator:** Wenquan Ou
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $235,233
- **Award type:** 5
- **Project period:** 2020-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10814962

## Citation

> US National Institutes of Health, RePORTER application 10814962, Nanotechnology for targeted therapy and fundamental understanding oftherapeutic resistance in triple negative breast cancer (5R01CA243023-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10814962. Licensed CC0.

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