Abstract 5046: Antimyeloma effect of proteasome inhibition and Parathyroid Hormone pathway

Abstract

Abstract Bone disease is a key feature in multiple myeloma (MM) and can impact substantially on patient morbidity and quality-of-life. Our recent studies have demonstrated specific serum Parathyroid Hormone (PTH) variations associated with proteasome inhibitor response in multiple myeloma patients. The rapid increase in PTH observed following bortezomib treatment suggests that the change in PTH could have triggered the significant osteoblastic response and bone anabolism. In this study we have tested the role of PTH and Parathyroid Hormone Receptor 1(PTHR1) after proteasome inhibition in vitro and in a mouse model.The effects of proteasome inhibition, PTH and {[TYR34]bPTH-(7-34)} compound (a specific PTH-(7-34) antagonist) were firstly evaluated at various concentrations and the same compounds and their combinations were also tested on C57BL/KaLwRij mouse model. Cell line viability, mice survival and myeloma response by serum IgG level were recorded. The 5TGM1 cell line was initially derived from a 5T33 myeloma cell line that arose spontaneously in aged C57BL/KaLwRij mice. The C57BL/KaLwRij mouse model is known for its spontaneous susceptibility to develop monoclonal gammopathies. The bone marrow of aging mice shows monoclonal expansion of plasmacells and skeletal radiography reveals osteoporosis with occasional osteolytic lesions. This model has been proved useful in studies on the effect of bisphosphonate in the treatment of bone disease in MM. The inoculation of 5TGM1 cells in the inbred C57BL/KaLwRij is able to rapidly induce a disease with similar features of human myeloma with severe osteolysis and Ig production and also with terminal involvement of nonbone organs including liver and kidney. We have first demonstrated the 5TGM1cell line is sensitivity to proteasome inhibition as well as PTH infusion in a dose-dependent fashion. 5TGM1 cells viability was not affected by exposure to {[TYR34]bPTH-(7-34)} peptide, a specific PTHR1inhibitor. We rather observed a suppression of bortezomib anti-myeloma effect when {[TYR34]bPTH-(7-34)} was used in combination (P = 0.0001).C57BL/KaLwRij mice treated with proteasome inhibitors showed a significantly prolonged survival benefit compared to controls (P = 0.04). When mice were concomitantly treated with a proteasome inhibitor and PTHR1 inhibitor, the survival benefit was completely abrogated. Similar results were observed in the serum IgG2b changes of the different cohorts of mice. The treatment with proteasome inhibitor, PTH or their combination induced a statistically significative decrease of IgG2b levels compared to controls (P = 0.02). These experiments strongly suggest that the proteasome inhibitory effect on myeloma growth in vitro and in mouse model is dependent on the PTHR1 pathway function. These data support a critical role of PTHR1 in the anti-myeloma effect associated with proteasome inhibition Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5046. doi:10.1158/1538-7445.AM2011-5046