# Direct therapeutic intervention of the tumor microenvironment with a potent inhibitor of fibronectin assembly

> **NIH NIH R21** · UNIVERSITY OF WISCONSIN-MADISON · 2021 · $176,980

## Abstract

PROJECT SUMMARY
Among the hallmarks of cancer, the extracellular matrix contributes to the regulation of each of the hallmark
principles underlying tumor progression. Importantly, extracellular matrix stiffness and fiber organization
enhance overall breast cancer progression and are associated with poor patient outcome. Biophysical and
biochemical cues from fibrillar matrix stiffness have emerged as key regulators of steps in the metastatic
cascade, including increased tumor cell invasion, inflammatory signaling, circulating tumor cells, and metastatic
outgrowth. Moreover, emerging studies demonstrate that biophysical cues from the ECM impact tumor intrinsic
and extrinsic factors implicated in immunotherapy resistance. Taken together, this data suggests that stromal
matrix stiffness may be one of the underlying mechanisms driving immunosuppression in the breast tumor
microenvironment. Despite the growing evidence that biophysical cues play a key role in disease progression
and the mounting interest in therapeutically targeting tumor ECM, there has yet to be an effective therapy directly
targeting the stromal matrix in breast cancer. Therefore, we propose to develop a therapeutically useful agent to
directly disrupt extracellular matrix assembly, deposition, and organization within the primary and metastatic
tumor microenvironments for the clinical treatment of breast cancer. We hypothesize that directly targeting
FN assembly with PEGylated-FUD will subsequently reduce tumor fibrosis by inhibiting collagen
deposition and fiber alignment resulting in decreased tumor growth and metastatic progression. We
further hypothesize that reduced fibronectin and collagen deposition will limit mechanical activation of pro-tumor
inflammation resulting in enhanced therapeutic efficacy in combination with immune checkpoint blockade. We
will test our hypothesis in the following aims: Aim 1: Determine the efficacy of PEGylated FUD as an anti-cancer
therapy in pre-clinical models of breast cancer. Aim 2. Evaluate the impact of PEGylated-FUD on
immunosuppressive signaling to enhance anti-PD-L1 therapy for treatment of metastatic disease.

## Key facts

- **NIH application ID:** 10199263
- **Project number:** 1R21CA252579-01A1
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** Glen S. Kwon
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $176,980
- **Award type:** 1
- **Project period:** 2021-06-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10199263

## Citation

> US National Institutes of Health, RePORTER application 10199263, Direct therapeutic intervention of the tumor microenvironment with a potent inhibitor of fibronectin assembly (1R21CA252579-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10199263. Licensed CC0.

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