# Engineering ferritin degrader-encapsulated platelets for post-surgical TNBC treatment

> **NIH NIH R01** · UNIVERSITY OF WISCONSIN-MADISON · 2024 · $542,721

## Abstract

PROJECT SUMMARY
As an aggressive and invasive type of breast cancer, triple-negative breast cancer (TNBC) has limited effective
treatment options in the clinic. Chemotherapy, represented by Taxol and Abraxane, is the first-line therapy for
TNBC, while TNBC patients who initially respond to chemotherapy will eventually develop drug resistance
following relapse. Immunotherapy, including immune checkpoint inhibitors, has only achieved success in treating
a small subset of patients with TNBC characterized by a high burden of somatic mutations. Surgery remains the
major treatment option for TNBC; however, the high frequency of TNBC recurrence after surgery could lead to
poor patient prognosis and high mortality. These highlight a critical unmet clinical need to develop a new
therapeutic modality that can serve as effective monotherapy or synergize with current first-line treatments to
prevent post-surgical TNBC recurrence. Intracellular ferritin serves as a key regulator to balance the increasing
need for iron to support TNBC growth while mitigating the damage of excess iron through mineralizing and
storing the intracellular iron ions. It has been well established that ferritin expression correlates positively with
TNBC cell proliferation, with more ferritin concentrations in TNBC tumors than in normal breast tissues. Clinically,
the serum ferritin level could serve as an indicator of disease severity in TNBC patients. In our preliminary studies,
we have developed a ferritin-degrading proteolysis targeting chimeras molecule (designated DeFer) that can
leverage the intracellular ubiquitin-proteasome system to degrade ferritin, leading to TNBC cell pyroptosis. In
vivo anti-TNBC efficacy was substantiated on 4T1 TNBC-bearing mice. Our study suggested that ferritin can
serve as a novel TNBC drug target, and its degradation could inhibit TNBC growth. In this proposal, we will
further optimize the developed DeFer, investigate the underlying ferritin degradation mechanisms, and test its in
vitro and in vivo anti-TNBC efficacy. Furthermore, to improve the in vivo pharmacokinetics and biodistribution of
DeFer, we will load DeFer into a platelet-based delivery system to improve the circulation time and facilitate the
selective accumulation at the post-surgical TNBC site. Finally, we will combine DeFer-loaded platelets with
immune checkpoint inhibitors to investigate the synergistic anti-TNBC recurrence efficacy on both murine TNBC
and human TNBC PDX models.

## Key facts

- **NIH application ID:** 10933130
- **Project number:** 1R01EB035992-01
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** Quanyin Hu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $542,721
- **Award type:** 1
- **Project period:** 2024-08-02 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10933130

## Citation

> US National Institutes of Health, RePORTER application 10933130, Engineering ferritin degrader-encapsulated platelets for post-surgical TNBC treatment (1R01EB035992-01). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10933130. Licensed CC0.

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