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William J. Gradishar, MD, FACP, FASCO


Combining p38i Inhibition and OX40 Agonist: Potential Therapy for Metastatic Breast Cancer

By: Amanda E. Ruffino, BA
Posted: Friday, March 24, 2023

Sheila A. Stewart, PhD, of Washington University School of Medicine in St. Louis, and colleagues conducted an investigation to identify the effectiveness of p38MAPKa inhibition (p38i) in limiting tumor growth and reprogramming the metastatic tumor microenvironment in patients with metastatic breast cancer. The team reported in Cancer Discovery that they have accomplished this by boosting the activity of macrophages and T cells and redirecting them to attack cancer cells that have metastasized.

“About 70% of patients with metastatic breast cancer have tumors that have spread to their bones. Our study suggests we may be able to use two treatments—one to sensitize the myeloid tumor microenvironment to immunotherapy, and one to activate T cells—to target these bone metastases in a way that eliminates the tumor, prevents the cancer from returning, and protects against bone loss in the process,” said Dr. Stewart in an institutional press release.

The researchers used a stromal labeling approach and single-cell RNA sequencing to identify targets that could increase the efficacy of p38i. They found that combining p38i and an OX40 agonist had a synergistic effect on reducing metastatic growth and increasing overall survival. Patients with a p38i metastatic stromal signature had better overall survival, and this was further improved by the presence of an increased mutational load. The investigators also reported that the combination of p38i, anti-OX40, and cytotoxic T-cell engagement cured mice of metastatic disease and produced long-term immunologic memory.

These findings demonstrate that a better understanding of the stromal compartment can help design effective antimetastatic therapies. The study also suggests that the combination of p38i, anti-OX40, and cytotoxic T-cell engagement may be a promising treatment for patients with antigenic breast cancer.

Disclosure: For full disclosures of the study authors, visit

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