# Targeted inhibition in stromal TGFβ activity in pancreatic cancer

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2020 · $374,691

## Abstract

Transforming growth factor β (TGFβ) is an attractive therapeutic target in cancer. However,
blocking TGFβ in pancreatic cancer (PDA) has not been successful in clinical studies. This is due
part to the fact that TGFβ signaling suppresses pancreatic cancer cell growth in a context-
dependent manner. In contrast, TGFβ signaling in stromal cells promotes to tumor progression
by inducing fibrosis and immunosuppression, characteristics of PDA. Moreover, we have
identified TGFβ-stimulated fibroblasts produce cytokines that limit innate immune cell activity. For
example, IL-6 production by PDA associated fibroblasts reduces NK cell activity that facilitates
PDA metastasis. Using species specific tools we demonstrated that selective inhibition of stromal
TGFβ signaling reduces PDA metastasis in mice bearing PDA xenografts and also promotes an
epithelial tumor cell phenotype and an altered immune microenvironment. These observations
strongly suggest a TGFβ-driven paracrine network between stromal cells and tumor cells in PDA
that promotes tumor progression. Up to 60% of human PDA have tumor cell specific deficiency in
canonical TGFβ signaling via loss of TGFβ receptor 2 (TGFβR2) or the downstream signal
mediator SMAD4. Here we propose that selective inhibition of TGFβ signaling in stromal cells in
PDA that harbors epithelial mutations in TGFβ signaling will dramatically and safely enhance the
efficacy of chemotherapy and/or immune therapy. To delineate the mechanisms involved and test
this novel strategy, we propose the following aims: 1, Identify TGFβ signaling in cancer associated
fibroblasts that drive PDA progression; 2, Determine the effect of stromal TGFβ inhibition on the
efficacy of chemotherapy and checkpoint blockade in models of TGFβ mutant PDA. If proven
correct this would provide a rationale to stratify PDA patients such that those with tumor cell
mutations in TGFβ signaling would be candidates for inhibition of stromal TGFβ signaling in
combination with standard therapy or immune therapy.

## Key facts

- **NIH application ID:** 10072860
- **Project number:** 1R01CA243577-01A1
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Rolf A Brekken
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $374,691
- **Award type:** 1
- **Project period:** 2020-07-06 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10072860

## Citation

> US National Institutes of Health, RePORTER application 10072860, Targeted inhibition in stromal TGFβ activity in pancreatic cancer (1R01CA243577-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10072860. Licensed CC0.

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