Overcoming Breast Cancer Metastasis to Bone by Cxcr2 Inhibition
Abstract
This project will 1) determine why/how breast cancer cells lie dormant for years and then re-emerge including determining how to prevent lethal recurrence; 2) identify why some breast cancers become metastatic; and 3) work towards eliminating the mortality associated with metastatic breast cancer. Avoiding the possibility of cancer recurrence at metastatic sites is the driving force behind many therapeutic strategies and is constantly on the minds of cancer patients. In breast cancer, the majority of breast cancers make estrogen receptor (ER+), which informs clinicians that the cancer cells grow in response to the hormone therapies, approximately 33% of these treated patients will develop recurrent metastatic tumors after hormone therapy. These recurrent tumors primarily metastasize to bone and either do not respond to or recur after current treatment options. The bone architecture gives cancer cells in bone an easy entryway to other tissues, ultimately increasing their spread throughout the body. To reduce patient mortality, we must determine why bone metastasis occurs and how to prevent it from occurring. Our research goal is to identify therapeutic strategies for patients with metastatic breast cancer. Recently, we developed a culture model in which we can grow mouse breast cancer cells within mouse bones. Using this model, we identified proteins, including specific proteins that are important in stimulating cancer cells to multiply. We identified therapies that target these proteins and significantly reduce the amount of cancer cells growing in bone. In the proposed research, we will determine how effective inhibiting these proteins is at stopping breast cancer metastasized to bone, particularly in ER+ tumors. Our hypothesis is that stopping one of these proteins (CXCR2) will be an effective therapeutic strategy that reverses breast cancer metastasized to bone. Drugs that stop CXCR2 are available but have not been tested against breast cancer metastasis to bone. We will evaluate these drugs for their efficacy both as single agents and in combination with standard of care treatments as new therapies to stop breast cancer that has metastasized to bone. If inhibiting CXCR2 reduces bone metastasis, then we will be in a position by the end of the grant period to propose that compounds that inhibit CXCR2 be used in a clinical trial of patients with stage IV metastatic ER+ breast cancer metastasized to bone. Therefore, this study will directly impact the design of such a clinical trial. The drugs that stop CXCR2 that are tested in our proposed study have already been used in clinical trials for other diseases, including prostate and ovarian cancers and pulmonary disease, and had few adverse responses and instead improved patient response, suggesting that they may also have low toxicity and have efficacy in patients. Since breast cancer tumors in bone typically do not respond well to current therapies and have few treatment options, this treatment strategy if successful would be significantly impactful to patients with ER+ breast cancer as a personalized therapy, bring significant hope, and improve the quality of life of patients with this disease. The therapies tested in this study then will be tested in future clinical trials aimed at not only stopping but ultimately curing bone metastasis in breast cancer patients with ER+ tumors.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110432
Entities
People
- Laurie Littlepage
Organizations
- United States Army
- University of Notre Dame