Therapeutic Targeting of Nonmalignant Accessory Cells in Bone Metastases of Hormone-Resistant ER-Positive Breast Cancer
Abstract
It is estimated that 39,620 women will die of breast cancer in the United States this year. Approximately 75% of all breast cancer patients have estrogen receptor (ER) detectable in their tumor cells (ER-positive breast cancer), and most breast cancer deaths occur among those ER-positive women. Breast cancer, typically, is non-fatal when it is confined to the breast or lymph nodes, as most deaths are due to the spread of the disease (metastases) to other parts of the body. For ER-positive breast cancers, bone is the most common site of metastasis. Although therapy can slow the progression of metastatic breast cancer in many cases, there is no cure for metastatic breast cancer, and the disease is often associated with debilitating pain and other symptoms. Our proposal addresses the overarching challenges of eliminating the mortality associated with metastatic breast cancer and identifying why some breast cancers become life-threatening metastases. Breast cancer metastasis is challenging to study in the laboratory, as most existing research models do not adequately replicate metastatic breast cancer. This limitation is particularly evident in ER-positive disease. Most mouse models engineered to develop breast cancer are not ER-positive and therefore do not simulate how ER-positive metastatic disease behaves, how it metastasizes to bones, and why it eventually becomes resistant to available treatments. Research models that replicate the characteristics of metastatic breast cancer are therefore needed to enable discovery and development of better treatments for metastatic disease and reduce deaths from cancer. While therapy resistance has been mainly attributed to mutations in breast cancer cells, evidence from our laboratory demonstrates that non-malignant cells in metastatic locations can protect tumor cells from diverse therapies and essentially function as "accessories" to and protectors of the tumor. We have developed a series of such preclinical laboratory and animal models to better simulate the clinical setting of metastases, and specifically study the role of bone "accessory" cells and how they trigger resistance of metastatic breast cancer cells to hormonal therapies, such as tamoxifen, raloxifene, and fulvestrant. The Partnering Principal Investigator has also developed computational approaches to model the molecular networks of pathways in breast cancer cells and in nonmalignant cells, tools that greatly facilitate investigation of the complex interactions between tumor cells and accessory cells. Our proposal will employ a synergistic computational and innovative experimental approach to study ER-positive breast cancer metastases to the bone. Using in vitro cell line models of ER-positive breast tumors and "accessory" nonmalignant cells from the bone, we will examine the impact that breast cancer cells have on these accessory cells and how they "hijack" them, using growth factors and direct interaction, in order to promote the survival and treatment resistance of the tumor. The genes, proteins, and molecular pathways that breast cancer cells use to manipulate the nonmalignant cells of the bone will be thoroughly analyzed and compared to a large database of gene expression profiles of patient tumors in order to prioritize the molecular targets and novel therapeutics that will be tested in preclinical animal models of ER-positive metastatic breast cancer to the bone. Our studies and their results will provide new information to advance the treatments and outcomes of patients with ER+ breast cancer who will or have developed metastases. We envision that the results of our studies will provide the basis for clinical trials of novel therapies for metastatic breast cancer and in adjuvant therapy of patients most at risk of developing metastatic breast cancer. We hope that the progress of our studies will allow such new therapeutic approaches to reach the stage of clinical trials very soon, ideally wit
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510012
Entities
People
- Constantine Mitsiades
Organizations
- Dana–Farber Cancer Institute
- United States Army