Targeting CaSR/GABAB R1 Heterodimers to Treat Bone Metastases in Breast Cancer
Abstract
Women die from breast cancer because of metastases, not because of their primary tumors. One of the most common sites of metastatic spread of breast cancer is the skeleton. Bone is the most common site of distant recurrence, and 70% of women with metastatic breast cancer have bone lesions. Estimates from 2012 Medicare statistics project that at least 108,000 US women currently have bone metastases. Although patients with only bone lesions survive longer than those with soft tissue metastases, bone metastases cause terrible pain, fractures, spinal cord damage, and high calcium levels. Current treatments with bisphosphonates and denosumab slow the progression of bone lesions, but they do not eliminate the cancer cells. Therefore, breast cancer is not curable once it has spread to the skeleton and, ultimately, bone metastases cause death. Approximately 28,000 women with breast cancer succumb to bone metastases each year. This is an unacceptable burden of suffering and death, and these statistics underscore the critical need for more effective treatments for bone metastases. In order for breast tumors to grow and expand in the skeleton, the cancer cells must co-opt the function of normal bone cells called osteoclasts. Osteoclasts are responsible for resorbing bone, and breast cancers attract these cells to enable the metastatic tumor to dissolve the mineralized bone and to excavate a cavity in which the tumor resides. However, when osteoclasts resorb bone, the surrounding calcium concentration near the tumor cells increases to very high levels. High extracellular calcium levels are toxic to normal breast cells, so breast cancer cells must adapt to high calcium concentrations if they are to grow well in bone. We believe that breast cancer cells do this by forming a heterodimer consisting of one extracellular calcium-sensing receptor (CaSR) together with one gamma-amino butyric acid B receptor 1 (GABAB R1). This hybrid receptor directs the cancer cells to proliferate instead of die when extracellular calcium increases. Our initial genetic techniques suggest that inhibition of this hybrid receptor complex can kill cancer cells when the extracellular calcium is elevated. In this proposal, we outline experiments to test whether antagonizing the heterodimeric receptor complex will prevent the growth of breast cancer cells in the presence of high extracellular calcium and whether inhibiting the heterodimeric receptor will kill breast cancer cells in animal models of bone metastases. As noted above, bone metastases are an important problem for breast cancer patients and we believe that targeting this new pathway will lead to the development of effective new therapies to kill bone metastases. Therefore, our proposal addresses the important challenge of eliminating mortality associated with metastatic breast cancer. We propose to carry out the necessary preclinical studies in cells and mice that are required to document whether this hybrid receptor complex is a valid drug target to kill breast cancer cells in bone. These studies hold the most immediate promise for patients that already have bone metastases and who, at present, have no options for curative therapy. However, our findings may ultimately also be applicable to attempts to prevent the formation of bone metastases in patients with disseminated tumor cells at the time of surgery. The CaSR and the GABAB R1 are both members of the G-protein coupled receptor (GPCR) family of cell-surface receptors. This is exciting because many successful drugs have been developed to target these types of receptors, making it likely that we could successfully develop drugs specific for the hybrid receptor. In recognition of this fact, we recently won a competition from the State of Connecticut funding the Yale Small Molecule Discovery Center and the UCONN Medicinal Chemistry Program to begin working with us to develop new drugs that would be specific for the hybrid recept
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610425
Entities
People
- John Wysolmerski
Organizations
- United States Army
- Yale University