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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA166060-01A1
Application #
8435146
Study Section
Skeletal Biology Development and Disease Study Section (SBDD)
Program Officer
Lively, Tracy (LUGO)
Project Start
2013-03-01
Project End
2018-02-28
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
1
Fiscal Year
2013
Total Cost
$300,543
Indirect Cost
$93,043
Name
University of Arkansas for Medical Sciences
Department
Orthopedics
Type
Schools of Medicine
DUNS #
122452563
City
Little Rock
State
AR
Country
United States
Zip Code
72205
Zangari, Maurizio; Yoo, Hanna; Shin, Ikjae et al. (2018) Thymic PTH Increases After Thyroparathyroidectomy in C57BL/KaLwRij Mice. Endocrinology 159:1561-1569
Zangari, Maurizio; Yoo, Hanna; Shin, Ik Jae et al. (2018) Surgical thyroparathyroidectomy prevents progression of 5TGM1 murine multiple myeloma in vivo. J Bone Oncol 12:19-22
Johnson, Rachelle W; Suva, Larry J (2018) Hallmarks of Bone Metastasis. Calcif Tissue Int 102:141-151
Kamalakar, Archana; Washam, Charity L; Akel, Nisreen S et al. (2017) PTHrP(12-48) Modulates the Bone Marrow Microenvironment and Suppresses Human Osteoclast Differentiation and Lifespan. J Bone Miner Res 32:1421-1431
Mohan, Meera; Samant, Rohan S; Yoon, Donghoon et al. (2017) Extensive Remineralization of Large Pelvic Lytic Lesions Following Total Therapy Treatment in Patients With Multiple Myeloma. J Bone Miner Res 32:1261-1266
Li, Juan; Pan, Qianying; Rowan, Patrick D et al. (2016) Heparanase promotes myeloma progression by inducing mesenchymal features and motility of myeloma cells. Oncotarget 7:11299-309
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
Zangari, Maurizio; Suva, Larry J (2016) The effects of proteasome inhibitors on bone remodeling in multiple myeloma. Bone 86:131-8
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
Stine, Kimo C; Wahl, Elizabeth C; Liu, Lichu et al. (2016) Nutlin-3 treatment spares cisplatin-induced inhibition of bone healing while maintaining osteosarcoma toxicity. J Orthop Res 34:1716-1724

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