IL-6/GP130 Signaling as a Novel Chemoprevention Target for Triple-Negative Breast Cancer
Abstract
The Goals: Triple-negative breast cancer accounts for 15%-20% of all breast cancer and is associated with poorer prognosis, earlier disease recurrence, and a higher incidence of metastasis compared to other subtypes of breast cancer. Due to the tumor s lack of estrogen receptors, progesterone receptors, and HER2 expression, women with triple-negative breast cancer are treated with chemotherapy as a neoadjuvant or adjuvant therapy. However, high-dose chemotherapy results in many side effects while eliciting limited efficacy against metastatic triple-negative breast cancer. Therefore, the goal of our study is to test a novel prevention strategy that has potential to be used to prevent triple-negative breast cancer further progression. To achieve our study goal, we plan to generate preclinical evidence to support future clinical utility of a novel chemoprevention agent using an oral drug bazedoxifene that has already been approved by the Food and Drug Administration (FDA) with an excellent safety profile. If proven effective in our preclinical studies, the drug may be moved to Phase I trials relatively quickly. Consequently, our application addresses the overarching challenge of “preventing breast cancer.” The Molecular Target: Interleukin-6 (IL-6) is a cytokine that signals through a heterodimeric IL-6Ralpha/GP130 complex and plays an important role in cancer progression. IL-6 is one of the principal oncogenic proteins in breast cancer, and serum IL-6 levels correlate with poor prognosis, advanced disease, and metastases. Our analysis of >500 breast tumor samples revealed that IL-6 pathway activation is enriched in triple-negative breast cancer and associated with a shorter time to develop metastasis compared to other subtypes. Importantly, triple-negative breast cancer cells secrete the highest levels of IL-6 compared to other subtypes of breast cancer, and the cell viability of triple-negative breast cancer cells rely on IL-6. Therefore, IL-6/GP130 signaling represents a novel target for chemoprevention in triple-negative breast cancer. To date, no IL-6/GP130-targeted small molecule drugs as chemoprevention agents are currently available for triple-negative breast cancer patients. Novel Prevention: Developing a brand-new drug to target IL-6/GP130 signaling could potentially take an enormous amount of money, time, and effort. Drug repurposing is an alternative strategy, which represents a shorter and easier path to clinical applications given known pharmacology, existing formulation, and excellent safety profile. Therefore, we screened FDA-approved drugs for their propensity to inhibit IL-6/GP130 signaling and have identified FDA-approved drug bazedoxifene as a novel inhibitor for the IL-6/GP130 signaling pathway. Bazedoxifene is marketed as DUAVEE (bazedoxifene with conjugated estrogens) for preventing postmenopausal osteoporosis. Bazedoxifene is a third-generation selective estrogen receptor modulator with improved uterine and ovarian cancer safety profile over Tamoxifen. Of note, there are currently 41 clinical trials using bazedoxifene or DUAVEE for postmenopausal osteoporosis, rheumatoid arthritis, and estrogen receptor positive breast cancer. Research Strategy: Building from our strong preliminary results from patient samples, triple-negative breast cancer cell lines, and mouse models of breast cancer growth and metastasis, we hypothesize that targeting the IL-6/GP130 signaling by bazedoxifene is a viable approach to prevent triple-negative breast cancer progression by blocking/preventing tumor growth, metastasis, and tumor recurrence after surgically removing the primary tumors. We will thoroughly test the hypothesis and evaluate this novel drug through cell-line, syngeneic/immunocompetent, and patient-derive xenograft (PDX) mouse models of triple-negative breast tumor growth to determine the prevention effects and organ-specific experimental metastasis mouse models to evaluate the impact of
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010045
Entities
People
- Jiayuh Lin
Organizations
- United States Army
- University of Maryland, Baltimore