# Development of a novel therapy targeting the tumor microenvironment in inflammatory breast cancer

> **NIH NIH R01** · UNIVERSITY OF HAWAII AT MANOA · 2023 · $581,465

## Abstract

PROJECT SUMMARY
Despite great promise, immune checkpoint inhibitors (ICIs) have had only modest impact on breast cancer
patients’ survival. Mechanistic studies into the interplay between the immune system and the tumor cells
identified the tumor microenvironment (TME) as the critical factor in dictating the impact of ICIs on tumor
progression. Clinical advancements in ICI efficacy will require combinations with agents that can induce a
broad shift in the microenvironmental milieu, which may prove especially important for highly aggressive
tumors. Inflammatory breast cancer (IBC) is a rare and highly lethal breast cancer with few therapeutic options.
In phase II clinical trial for triple-negative IBC patients, we found that anti-EGFR antibody panitumumab
(PmAb) combined with preoperative chemotherapy led to a high treatment response. We further found that in
IBC models, PmAb reduced the expression of immunosuppressive chemokines and led to increased infiltration
of cytotoxic T cells; suggesting a broad shift from an immunosuppressive to immunoreactive TME. Building on
these preliminary findings, we propose to determine the mechanism by which EGFR promotes the expression
of immunosuppressive chemokines and if, in turn, this effect is responsible for the observed
immunosuppressive TME in IBC. While EGFR inhibition has been examined as a way to target tumor cell
proliferation and survival, to our knowledge, no other group has examined EGFR as a modulator of the TME in
IBC. We propose 3 aims: Aim 1: Determine the mechanism by which the EGFR pathway modulates the
TME in IBC. We hypothesize that the EGFR pathway induces an immunosuppressive TME in IBC through
EGR1-regulated expression of immunosuppressive chemokines. We will test this hypothesis via in vitro assays
and our novel humanized IBC immunocompetent mouse model. Aim 2: Evaluate the combination of
immunotherapy with EGFR inhibition in IBC. We hypothesize that EGFR-targeted therapy will enhance the
efficacy of immunotherapy in IBC by shifting the TME from an immunosuppressive to an immunoreactive
phenotype. We will test the efficacy of targeting EGFR and inhibiting immune checkpoints in combination using
the novel IBC humanized mouse model and triple-negative breast cancer immunocompetent mouse models
with intrinsic and acquired resistance to ICIs. Aim 3: Determine the clinical relevance of EGFR-modulated
TME changes in IBC. We hypothesize that reduced expression of EGR1 and its likely transcriptional targets
correlates with TME immunoreactive status and predicts IBC patient response to PmAb-based therapies. We
will assess the clinical relevance of our pathway using an IBC genomic dataset and multiplexed
immunostaining on an IBC tissue microarray and IBC tissues from an ongoing PmAb clinical trial. Upon
completion, we expect to identify TME changes that predict patient response to EGFR-targeted therapy and
establish a novel EGFR-based combination therapy with ICIs for patients with IBC. Beyond IB...

## Key facts

- **NIH application ID:** 10836263
- **Project number:** 7R01CA258523-02
- **Recipient organization:** UNIVERSITY OF HAWAII AT MANOA
- **Principal Investigator:** Naoto T. Ueno
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $581,465
- **Award type:** 7
- **Project period:** 2022-03-01 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10836263

## Citation

> US National Institutes of Health, RePORTER application 10836263, Development of a novel therapy targeting the tumor microenvironment in inflammatory breast cancer (7R01CA258523-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10836263. Licensed CC0.

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