Influence of simultaneous targeting of the bone morphogenetic protein pathway and RANK/RANKL axis in osteolytic prostate cancer lesion in bone

Abstract

Metastasis to bone is the leading cause of morbidity and mortality in advanced prostate cancer patients. Considering the complex reciprocal interactions between the tumor cells and the bone microenvironment, there is increasing interest in developing combination therapies targeting both the tumor growth and the bone microenvironment. In this study, we investigated the effect of simultaneous blockade of BMP pathway and RANK-RANKL axis in an osteolytic prostate cancer lesion in bone. We used a retroviral vector encoding noggin (Retronoggin) to antagonize the effect of BMPs and RANK: Fc, which is a recombinant RANKL antagonist was used to inhibit RANK-RANKL axis. The tumor growth and bone loss were evaluated using plain radiographs, hind limb tumor measurements, micro PET-CT ( 18 F-fluorodeoxyglucose [FDG] and 18 F-fluoride tracer), and histology. Tibias implanted with PC-3 cells developed pure osteolytic lesions at 2 weeks with progressive increase in cortical bone destruction at successive time points. Tibias implanted with PC-3 cells over expressing noggin (Retronoggin) resulted in reduced tumor size and decreased bone loss compared to the implanted tibias in untreated control animals. RANK: Fc administration inhibited the formation of osteoclasts, delayed the development of osteolytic lesions, decreased bone loss and reduced tumor size in tibias implanted with PC-3 cells. The combination therapy with RANK: Fc and noggin over expression effectively delayed the radiographic development of osteolytic lesions, and decreased the bone loss and tumor burden compared to implanted tibias treated with noggin over expression alone. Furthermore, the animals treated with the combination strategy exhibited decreased bone loss (micro CT) and lower tumor burden (FDG micro PET) compared to animals treated with RANK: Fc alone. Combined blockade of RANK-RANKL axis and BMP pathway resulted in reduced tumor burden and decreased bone loss compared to inhibition of either individual pathway alone in osteolytic prostate cancer lesion in bone. These results suggest that †Corresponding author's address:

Upregulation of CRMP4, a new prostate cancer metastasis suppressor gene, inhibits tumor growth in a nude mouse intratibial injection model

“…In our research, we find that both PC3 and DU145 express no SDF-1 gene and low expression of CXCR4 mRNA, and CRMP4 overexpression did not affect CXCR4 mRNA expression. OPG/ RANKL signaling is an important regulator of osteolytic/ osteoblastic balance in bone (34) and it has been shown that OPG and RANKL are key factors mediating osteolytic bone injury in prostate cancer bone metastasis (35). Our research showed both cell lines express OPG and RANKL at a low mRNA lever but these factors are not affected by CRMP4 overexpression (Fig.…”

Recent advances in bone-targeted therapies of metastatic prostate cancer

“…In an osteolytic SCID mouse model of bone metastasis induced by intratibial injection of PC-3 cells, Virk et al studied the effect of simultaneous blockade of the RANK/RANKL axis using subcutaneous administration of RANK-Fc and the BMP pathway using retrovirus-mediated overexpression of noggin, a cognate binding protein and an antagonist of BMP4. The combination therapy with RANK-Fc and noggin effectively delayed the development of osteolytic lesions and decreased the bone loss and tumor burden compared with noggin overexpression alone (32). Further, in a mixed lytic/blastic PCa lesion in bone induced by intratibial injection of C42b cells, the same group found that treatment with both RANK-Fc and noggin demonstrated delayed development of bone lesions, attenuation of osteolysis, inhibition of small soft tissue tumors, and preservation of bone architecture with less tumor-induced new bone formation (33).…”

RANKL inhibition: Clinical implications for the management of patients with multiple myeloma and solid tumors with bone metastases

“…The combination therapy with RANK-Fc and noggin over expression effectively delayed the radiographic development of osteolytic lesions, and decreased the bone loss and tumor burden compared with tibias with implants treated with noggin overexpression alone. Furthermore, the animals treated with the combination strategy exhibited decreased bone loss and lower tumor burden compared with animals treated with RANK-Fc alone [78]. The results of the above studies suggest that simultaneous targeting of tumor cells and osteoclasts may be the most effective method of inhibiting the progression of established osteolytic metastatic lesions in vivo and provided the rationale for using such combinations in humans.…”