Our application entitled "Breast Cancer Bone Metastasis" is focused on the characterization of specific biomarkers (PTHrP(12-48) and IL-8) that we have identified in the circulation of breast cancer patients with bone metastasis. Currently, a barrier to understanding and treating diseases of interest to NIH/NCI, such as breast cancer bone metastasis, is the paucity of sensitive and specific biomarkers. The biomarker profile we have identified and validated contains PTHrP(12-48) and IL-8 and discriminates breast cancer patients with and without bone metastasis with a sensitivity and specificity of (98% and 82% respectively). These molecules have the potential to increase the accuracy of bone metastasis diagnosis in the clinical setting, provide new mechanistic insight into tumor-induced changes in bone metabolism and possibly even improve the assessment of breast cancer bone metastasis patient outcomes.
Aim 1 will improve our existing assay and measure PTHrP(12-48) and IL-8 in patient plasma and human breast cancer specimens.
Aim 2 will explore the mechanism of action of tumor-derived IL-8 in the regulation of osteoclastogenesis. Importantly, we will also obtain genetic evidence for direct effects of IL-8 on osteoclast formation in vivo and determine if IL-8 expression can rescue the osteopetrotic bone phenotype of RANKL-/- mice.
Aim 3 will correlate other clinically relevant parameters such as survival, tumor burden and time-to-next SRE with our existing proteomic dataset, and then independently validate and identify the correlated biomarkers using untested archival patient plasma. The studies proposed will significantly impact the field by providing new information regarding the progression of breast cancer bone metastasis. If successful clinically, PTHrP(12-48) and IL-8 have the potential to be utilized as biochemical markers for the evaluation of breast cancer bone metastasis that may predict breast cancer burden and possibly even patient survival.
The long-term goal of our research is to identify the circulating biomarkers in breast cancer patients that predict the development of bone metastasis. We have identified two such circulating biomarkers (PTHrP(12- 48) and IL-8). Currently, the diagnosis of bone metastasis usually involves a PET or bone scan, which cannot detect a metastasis until it is ~7mm. As such, the studies we propose will identify the tumor-derived IL-8 signaling pathways that directly regulate osteoclastogenesis and have the potential to provide a more sensitive and specific test for the detection of breast cancer bone metastasis.
|Suva, Larry J; Gaddy, Dana (2016) Back to the Future: Evaluation of the Role of Glutamate in Bone Cells. Calcif Tissue Int 99:112-3|
|Makhoul, Issam; Montgomery, Corey O; Gaddy, Dana et al. (2016) The best of both worlds - managing the cancer, saving the bone. Nat Rev Endocrinol 12:29-42|
|Suva, Larry J; Makhoul, Issam (2015) Bone: Will breast cancer chemoprevention stand on 'solid bone'? Nat Rev Endocrinol 11:138-9|
|Fowler, Tristan W; Kamalakar, Archana; Akel, Nisreen S et al. (2015) Activin A inhibits RANKL-mediated osteoclast formation, movement and function in murine bone marrow macrophage cultures. J Cell Sci 128:683-94|
|Kamalakar, Archana; Bendre, Manali S; Washam, Charity L et al. (2014) Circulating interleukin-8 levels explain breast cancer osteolysis in mice and humans. Bone 61:176-85|
|Zangari, Maurizio; Berno, Tamara; Yang, Ye et al. (2014) Parathyroid hormone receptor mediates the anti-myeloma effect of proteasome inhibitors. Bone 61:39-43|