Targeting Treatment Resistance in Patients with Metastatic ER-Positive Breast Cancer
Abstract
Background: Approximately 75% of all breast cancers are estrogen receptor (ER)-positive. Hormone therapies, which block ER signaling, and CDK4/6 inhibitors, which prevent the cell from dividing, are used are the preferred treatment for ER-positive breast cancer patients with disseminated disease. While these treatments are quite effective in controlling the cancer initially, virtually all patients with disseminated breast cancer ultimately become unresponsive/resistant to these drugs. Treatment options for such patients are severely limited. Therefore, there is an urgent need to develop new treatments that overcome resistance to both hormone therapies and CDK4/6 inhibitors and improve survival in these patients. In this proposal, we establish model systems to study how breast cancer patients develop resistance to hormone therapies and CDK4/6 inhibitors. Using a combination of gene editing approaches in breast cancer cell lines and tumors samples collected from patients who have become unresponsive to these drugs, we built a platform of treatment-resistant breast cancel models that faithfully recapitulate the characteristics of similar tumors in breast cancer patients. We use these innovative models to study how these cancers undergo alterations in their 3D DNA architecture and DNA repair pathways to develop resistance. Based on our prior work and a drug screen using nearly 1200 Food and Drug Administration-approved drug collection, we show that OTX015, a new drug under development, is highly effective in preventing the growth of these resistant cancers, both in a dish and when implanted in mice. OTX015 inhibits bromodomain and extra-terminal domain (BET) family of proteins and blocks the pathways that are reprogrammed in the unresponsive tumors. In this proposal, we will carry out mechanistic studies that will help understand which patients will benefit from treatment with this new class of drugs. We have also identified several novel drug combinations that significant improve the efficacy of the treatments and will validate them in a large panel of mice bearing various unresponsive tumors. Thus, we identify what drives breast cancer growth (unresponsiveness to endocrine therapies and CDK4/6 inhibitors), and determine how to stop it (by targeting treatment resistance with OTX015, a drug that inhibits the function of BET family of proteins). We will revolutionize treatment regimens by replacing chemotherapy with a new targeted therapy (BET inhibitor), which is more effective, less toxic, and improves survival. In summary, we introduce a new paradigm for treatment of metastatic, ER-positive breast cancer patients, who have become resistant to currently available targeted therapies. There are 200,000 women living with metastatic breast cancer in the United States. Nearly 75% of these women harbor ER-positive breast cancer. Virtually, all ER-positive, metastatic breast cancer patients eventually develop resistance to both endocrine therapies and CDK4/6 inhibitors. There are currently limited or no targeted therapy options for women with treatment-refractory breast cancer, and chemotherapy (which is less effective and more toxic) remains the main systemic therapy in such patients. Pharmacological BET inhibition with OTX015, which overcomes resistance to both endocrine therapies and CDK4/6 inhibitors, has the potential to transform the landscape of metastatic, ER-positive breast cancer treatment, and substantially improve breast cancer mortality. Since the BET inhibitor employed in this study, OTX015, has shown a favorable safety profile in a recently concluded Phase I clinical trial, successful completion of goals outlined in this proposal will expedite clinical evaluation of OTX015 in treatment-refractory ER-positive breast cancers, paving the way for significant improvement in breast cancer survival.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110114
Entities
People
- Ram S Mani
Organizations
- United States Army
- University of Texas Southwestern Medical Center