# Aptamer mediated silencing of the spliceosome machinery to increase the immunogenicity of metastatic breast cancer

> **NIH NIH R21** · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · 2022 · $210,978

## Abstract

Even with the FDA approval of Atezolizumab in combination with nab-Paclitaxel for PDL1 positive triple
negative breast cancer, metastatic breast cancer is still a deadly disease. The modest impact of checkpoint
inhibitor therapy in this disease can be partially explained by the relatively low tumor mutation burden, by the low
expression of neoantigens and the overall low immunogenicity of metastatic breast cancer compare to other
malignancies in which checkpoint inhibitors are highly effective. Recent RNA sequencing and MHC-peptidome
analyses of tumors from patients undergoing checkpoint inhibition therapy revealed the important contribution of
intron-derived epitopes in the neoantigen pools. In breast cancer these intron-derived neoantigens are poorly
expressed because of the constitutive upregulation of the spliceosome machinery.
 Here we will test the hypothesis that aptamer mediated targeted silencing snRPE, a key component of
the spliceosome machinery, can increase breast cancer immunogenicity and synergize with anti-PD1 in the
eradication of metastatic breast cancer. Toward this targeted therapy, we have identified two RNA aptamers
that can recognize and mouse and human metastatic breast cancer cells in vitro and in vivo. RNA aptamers are
small oligonucleotides that because of their 3D structure can recognize their ligand with high affinity. Aptamers
are chemically synthetized with a backbone that confer RNAse resistance and lack of immunogenicity and can
be modified for improved pharmacokinetic and for therapeutic delivery. We have conjugated our aptamer with
siRNA against snRPE and showed their in vitro efficacy.
 In this study, we will employ two aggressive model of mouse breast cancer: the 4T1 and the E0771 in
two different genetic backgrounds. First, we will characterize the role of the immune system in the antitumor
response using NSG and immune competent mice, depletion experiments, and by characterizing the tumor
microenvironment and the anti-tumor immunity. Then, we will measure the therapeutic effect of aptamer chimera
as monotherapy or in conjunction with checkpoint inhibition therapy and vaccination against intron derived
neoepitopes for the treatment of metastatic breast cancer.
 We expect that this treatment will be well tolerated and will increase tumor immunogenicity and the
efficacy of checkpoint inhibition therapy. Since our aptamers recognize both mouse and human metastatic
cancers, the translation of positive finding in the clinic might should be facilitated and might have, in the future,
an important impact on metastatic breast cancer allowing its eradication and/or containment with minimal side
effect.

## Key facts

- **NIH application ID:** 10461876
- **Project number:** 5R21CA263607-02
- **Recipient organization:** UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
- **Principal Investigator:** Paolo Serafini
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $210,978
- **Award type:** 5
- **Project period:** 2021-08-04 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10461876

## Citation

> US National Institutes of Health, RePORTER application 10461876, Aptamer mediated silencing of the spliceosome machinery to increase the immunogenicity of metastatic breast cancer (5R21CA263607-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10461876. Licensed CC0.

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