Targeting p38gamma for the Treatment of Triple-Negative Breast Cancer
Abstract
Triple-negative breast cancer (TNBC) lacks protein expression of estrogen receptor (ER), progesterone receptor (PR), and epidermal growth factor receptor 2 (Her-2) for therapeutic targeting. Consequently, TNBC has the worst prognosis among all types of breast cancers. Currently, chemotherapy remains the main treatment option for TNBC, which however is inevitably associated with life-threatening toxicities such as gastrointestinal complications, bleeding, lung fibrosis, and cardiotoxicity. Moreover, the majority of patients treated with chemotherapy suffer from hair loss, which represents one of the most distressing side effects. The objective of this proposal is to development safe and targeted therapies for TNBC by addressing the overarching challenge "revolutionizing treatment regimens by replacing interventions that have life-threatening toxicities with ones that are safe and effective." Cancer stem-like cells (CSCs) represent a sub-population of cells with high self-renewal capacity and tumor-initiating properties that is exchangeable with its non-CSC component. Accumulating evidence indicates that CSCs are involved in oncogenesis and tumor progression, and targeting CSC may have important implications in cancer therapy. Although CSC is enriched in TNBC, its druggable molecular drivers are mostly unknown. p38gamma MAPK (gene name: MAPK12) is an established breast cancer metastatic gene that is overexpressed in TNBC. Moreover, p38gamma overexpression is associated with decreased patient survival, but the mechanism by which activated p38gamma contributes to TNBC remains a mystery. This proposal will test the hypothesis that p38gamma promotes TNBC development and progression by stimulating CSC expansion. This hypothesis is based on our preliminary studies showing that p38gamma-forced expression stimulates CSC expansion, induces experimental TNBC, and increases breast cancer invasion/metastasis. Moreover, we showed that targeting p38gamma by pharmacological and genetic tools reduces CSC population, selectively blocks TNBC growth, and decreases levels of Nanog and other CSC-driven transcription factors. Together, these results indicate that p38gamma activation triggers TNBC development and progression by stimulating CSC expansion. This hypothesis will be tested in experimental cell lines and in clinical breast cancer specimens with the main focus to develop novel therapeutics for TNBC. Upon completion, these studies will demonstrate that p38gamma MAPK is a novel TNBC oncogene by stimulating CSC population through the c-Jun/Nanog pathway. The significance of this study is further highlighted by the current availability of the non-toxic and Food and Drug Administration-approved p38gamma specific pharmacological inhibitor pirfenidone (for the treatment of lung fibrosis). Demonstration of the role of p38gamma activation in driving and converting CSC expansion to TNBC development and progression will have immediate application potentials. Our results will demonstrate if the p38gamma inhibitor pirfenidone can be repurposed as a novel therapeutic agent for TNBC by depleting CSC.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 29, 2016
- Source ID
- W81XWH1510307
Entities
People
- Guan Chen
Organizations
- Medical College of Wisconsin
- United States Army