# Nanoparticles-mediated combination therapy for breast cancer

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2024 · $476,617

## Abstract

Abstract
Despite recent advances in treatment, metastatic breast cancer (mBCa) remains one of the leading causes of
cancer-related deaths in the United States among women. Chemotherapy remains fundamental to the
management of all molecular subtypes of mBCa and anthracyclines and taxanes are two major types of
chemotherapeutics. One major issue in chemotherapy is drug resistance, both intrinsic and acquired. In addition,
the overall benefit of immunotherapy remains limited for mBCa. There is still a need to develop novel strategies
to overcome chemoresistance and/or the poor response of immunotherapy in mBCa. IRhom proteins (iRhom 1
and iRhom 2) are catalytically inactive relatives of rhomboid intramembrane proteases and play an important
role in regulating the stability and trafficking of other membrane proteins. IRhom1 is overexpressed in several
types of cancers including breast cancer (BCa) and knockdown of iRhom1 led to significant inhibition of tumor
growth in vivo. We have shown that knockdown of iRhom1 led to sensitization of tumor cells to several
chemotherapeutic agents including doxorubicin (DOX) and SAHA. We have further shown that iRhom1 plays a
role in modulating tumor immune response and knockout of iRhom1 resulted in an improvement in tumor immune
microenvironment. To facilitate the therapeutic translation of these novel findings, we have developed a new
nanocarrier that is highly effective in selective codelivery of iRhom1 siRNA and chemotherapeutic agents to
tumors. We have also developed a bioengineered iRhom1 pre-siRNA (pre-siiRhom1) that is biotransformed to
mature siRNA upon intracellular delivery. We have further developed DOX-SAHA, a prodrug conjugate to
facilitate codelivery of the two drugs of synergistic action. This application is focused on further improvement of
the safety and the tumor-targeting efficiency of the nanocarrier as well as the overall therapeutic efficacy of
codelivery of DOX-SAHA/pre-siiRhom1. The underlying mechanism will also be investigated. Three specific aims
will be pursued in this proposal. Aim 1 will develop and characterize an improved nanocarrier for co-formulating
DOX-SAHA and pre-siiRhom1. Aim 2 will investigate the tumor-targeting efficiency of the nanocarrier, and the
PK and tissue biodistribution of DOX-SAHA and pre-siiRhom1 co-formulated in the nanocarrier. Aim 3 will
investigate the in vivo therapeutic efficacy, the underlying mechanism, and the toxicity profile of the combination
therapy in murine and human BCa models. Successful completion of this study will lead to the development of
a new combination therapy for the treatment of different types of cancers including mBCa.

## Key facts

- **NIH application ID:** 10831461
- **Project number:** 5R01CA278608-02
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Song Li
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $476,617
- **Award type:** 5
- **Project period:** 2023-05-01 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10831461

## Citation

> US National Institutes of Health, RePORTER application 10831461, Nanoparticles-mediated combination therapy for breast cancer (5R01CA278608-02). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10831461. Licensed CC0.

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