RAGE: A Novel Therapeutic Target Against Metastatic and Triple-Negative Breast Cancer
Abstract
The overarching challenge of this proposal is to (a) identify why some breast cancer subtypes become more metastatic and (b) eliminate the mortality associated with metastatic breast cancer. It’s estimated that at least 154,000 people in the U.S. have metastatic breast cancer. Metastasis is a major cause of mortality in breast cancer patients, in part due to the lack of clinically established targeted therapies. Approximately 5%-20% of patients with stage II and ~50% of patients with stage III will recur distally and are likely to die from their disease. Metastatic, or stage IV, breast cancers have a 5-year relative survival rate of about 22%. Among the different types of breast cancers, triple-negative breast cancer (TNBC) has been associated the most with poor prognosis and survival due to the lack of clinically established targeted therapies and distant metastasis. In addition, TNBC has been shown to develop early metastasis to the lungs and other organs. Hence, uncovering a means of inhibiting metastatic breast cancer including TNBC, using safer, less toxic, and more effective drugs, would be a significant advancement in the treatment of aggressive breast cancers. In our preliminary data, we have shown that an inflammatory molecule, receptor for advanced glycation end products (RAGE), is highly expressed in TNBC cells and in the tumors of a small cohort of TNBC and metastatic breast cancer patients. In addition, we have observed from publically available databases that breast cancer patients expressing higher RAGE have worse prognosis and poorer survival. In this proposal, we will analyze the expression of RAGE in a large cohort of TNBC and invasive breast cancer patient samples and correlate it with different clinical parameters, including survival. This will help to establish novel diagnostic biomarkers and therapeutic targets against aggressive and metastatic breast cancers, including TNBC. We have also shown that genetically knocking out RAGE in a mouse model reduces breast tumor growth and subsequent metastasis. In addition, we have shown that blocking RAGE by neutralization antibody significantly inhibits metastasis in mice. In this proposal, we will further analyze the therapeutic potential of anti-RAGE agents on TNBC progression and metastasis in human and mouse TNBC preclinical models. One prominent feature of the TNBC is expression of EGFR. Since the majority of patients develop resistance to anti-EGFR therapies, it is important to understand the signaling pathways downstream of EGFR in TNBC to develop new therapies and thereby circumvent EGFR resistance. We have also shown that RAGE may increase the metastatic potential of TNBC cells by enhancing EGFR signaling. In this proposal, we will further define the RAGE-mediated signaling mechanisms in tumor cells that enhance tumor growth and metastasis, especially their role in enhancing EGFR signaling. We also hypothesize that RAGE present on immune cells suppresses anti-tumor immune responses by subverting the function of immune cells, especially tumor associated macrophages (TAMs) that surround the tumor. TAMs are the major host component contributing to the anti-tumor immunity suppression. These cells are often associated with poor prognosis in breast cancer, especially TNBC. Therefore, inhibition of TAM recruitment and accumulation is a promising strategy to target breast cancer progression and metastasis, and to enhance the effectiveness of immune-based therapies against tumors. In this proposal, we will further define the role of RAGE in enhancing the TAMs that show pro-tumor activity. These studies will help us determine if anti-RAGE agents can be used to enhance immune responses against TNBC and prevent its metastasis. Overall, these studies will help us to develop innovative targeted and immune-based therapies for TNBC, whose devastating prognosis is due to early metastasis to other organs and a lack of clinically establishe
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jul 16, 2019
- Source ID
- W81XWH1910088
Entities
People
- Ramesh K. Ganju
Organizations
- Ohio State University
- United States Army