Identification of Therapeutic Vulnerabilities in ER+/RB1-Deficient Breast Cancers
Abstract
Breast cancer accounts for over 42,000 deaths each year in the United States. Approximately 70% of breast cancer-related deaths occur in patients with the estrogen receptor-positive (ER+) breast cancer subtype. Growth of ER+ breast tumors relies heavily on two molecules, called CDK4 and CDK6. Recently, the approval and clinical use of CDK4/6 inhibitors (CDK4/6i) have significantly prolonged progression-free and overall survival of patients with advanced ER+ breast cancer. Unfortunately, the therapeutic benefit of CDK4/6i is transient, as all tumors eventually develop drug resistance. Clinical studies have reported that loss of the tumor suppressor gene RB1, through mutations or other mechanisms, confers resistance to CDK4/6i. We estimate that there are over 10,000 patients with ER+ breast cancer harboring RB1 mutations in the U.S. This patient population is expected to keep rising in the near future because CDK4/6i are now given routinely to patients with advanced ER+ breast cancer. To date, the lack of effective treatments for ER+/RB1-deficient breast cancer remains an unmet medical need. The central goal of this project is to identify novel molecular targets and therapeutic strategies that effectively treat patients with ER+/RB1-deficient breast cancer. We generated ER+/RB1-deleted breast cancer cell models to mimic RB1 loss-of-function mutations in ER+ breast cancer. We used these cells to test 19,114 genes and discovered that depletion of two of the top hits, CARM1 and PRMT5, dramatically inhibited the growth of ER+/RB1-deficient breast cancer cells. Based on these exciting results, we aim to study the functions of CARM1 and PRMT5 and effective ways to inhibit in order to block tumor growth. To achieve the goals of this project, we will use breast cancer cell lines and human breast tumors grown in mice to study why CARM1 and PRMT5 are important for tumor growth. Additionally, we will test if CARM1 or PRMT5 inhibitors can effectively block the growth of ER+/RB1-deficient tumors in mice. Taken together, these research aims will determine if CARM1 and PRMT5 are therapeutic targets for the treatment of ER+/RB1-deficient breast cancer. We are optimistic that successful completion of this project can lead to clinical trials testing CARM1 or PRMT5 inhibitors in patients within three to four years. Impact on BCRP s mission of ending breast cancer: This project will identify innovative approaches to effectively treat patients with ER+/RB1-deficient breast cancer. We believe this research proposal will have significant impact on several overarching challenges: (1) Identify what drives breast cancer growth and determine how to stop it, and (2) Reduce the mortality associated with metastatic breast cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210144
Entities
People
- Chang-ching Lin
Organizations
- United States Army
- University of Texas Southwestern Medical Center