Prevention of Breast Cancer Skeletal Metastases with Parathyroid Hormone
Abstract
This proposal seeks to address the overarching challenge of identifying why some breast cancers become metastatic. Breast cancer is the most common cancer among women, and the second leading cause of cancer deaths. Although we have made great strides in treating breast cancer when it is detected early, by the time breast cancer has spread to distant organs, it is invariably incurable. The skeleton is one of the more frequent sites affected by the spread of breast cancer, leading to debilitating pain, fractures, and possibly spinal cord damage. Breast cancer spreads so easily to bone because the skeleton produces many factors that attract cancer cells. Under normal circumstances, the bone marrow is also the site of blood cell production, and bone-forming osteoblasts serve an important role in supporting the formation of blood cells. It turns out that many of the factors that are produced by bone to assist in blood cell production are also involved in attracting breast cancer cells to the skeleton. Therefore, studying the support of blood production by bone may lead us to better understand breast cancer metastases to the skeleton. Furthermore, medications for the treatment of osteoporosis, a disease of fragile bones, may also be beneficial in preventing the spread of breast cancer to bone. Osteoporosis is common among breast cancer patients. In the general population, half of all women over the age of 50 are expected to sustain a fracture due to weak bones in their lifetime. In breast cancer patients, many factors can further worsen bone loss. The stress of chemotherapy leads to premature menopause, with accelerated decline in bone mineral density. In patients with estrogen receptor-positive breast cancer, treatment with medications to fully block the effects of estrogen (aromatase inhibitors) can significantly reduce breast cancer recurrence, but also cause bone loss. Zoledronic acid and other similar medications have proven very effective and are commonly used in women with breast cancer. However, not all patients benefit from these medicines -- they cannot be used in those with kidney disease, and there are some concerns about potential long-term side effects. If additional medications to treat osteoporosis are found to be safe in breast cancer patients, this would provide patients and their physicians a greater range of options for optimizing skeletal health. Parathyroid hormone (PTH) regulates the body s calcium levels. When PTH is given once a day, it can also profoundly stimulate bone formation, and this is now available as the medication teriparatide for the treatment of osteoporosis. Right now it is the only medical treatment that increases bone formation and therefore could be useful for breast cancer patients. However, the safety of PTH in breast cancer patients is unknown. In mice, PTH acts on the skeleton to increase support of hematopoietic stem cells, which give rise to all the blood cell types in the body. If cancer cells are like stem cells, then cancer stem cells might override the interactions between normal blood cells and the bone, and PTH might promote breast cancer skeletal metastases, an undesirable outcome. However, it is also possible that PTH may favor normal blood cells over cancer cells and instead reduce bone metastases. In either case, it is important for physicians to understand the safety and utility of PTH in patients with breast cancer. We have performed pilot studies in mice and found that in mice with breast cancer, PTH decreases the spread of cancer cells to bones. This is true both when we implant breast cancer cells into the breast and allow it to metastasize to the skeleton, as well as when we inject breast cancer cells into the bones of mice. In this application, we will evaluate whether PTH started after breast cancer has been established can still reduce the spread of cancer to bone. We also propose experiments to understand how PTH works to cause th
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1710027
Entities
People
- Joy Wu
Organizations
- Stanford University
- United States Army