Apo2l/Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand Prevents Breast Cancer–Induced Bone Destruction in a Mouse Model

Abstract

Breast cancer is the most common carcinoma that metastasizes to bone. To examine the efficacy of recombinant soluble Apo2 ligand (Apo2L)/tumor necrosis factor-related apoptosisinducing ligand (TRAIL) against breast cancer growth in bone, we established a mouse model in which MDA-MB-231 human breast cancer cells were transplanted directly into the marrow cavity of the tibiae of athymic nude mice producing osteolytic lesions in the area of injection. All vehicle-treated control animals developed large lesions that established in the marrow cavity, eroded the cortical bone, and invaded the surrounding soft tissue, as assessed by radiography, micro-computed tomography, and histology. In contrast, animals treated with recombinant soluble Apo2L/TRAIL showed significant conservation of the tibiae, with 85% reduction in osteolysis, 90% reduction in tumor burden, and no detectable soft tissue invasion. Tumor cells explanted from Apo2L/TRAIL-treated animals were significantly more resistant to the effects of Apo2L/TRAIL when compared with the cells explanted from the vehicle-treated control animals, suggesting that prolonged treatment with Apo2/TRAIL in vivo selects for a resistant phenotype. However, such resistance was readily reversed when Apo2L/TRAIL was used in combination with clinically relevant chemotherapeutic drugs, including taxol, etoposide, doxorubicin, cisplatin, or the histone deacetylase inhibitor suberoylanilide hydroxamic acid. These studies show for the first time that Apo2L/TRAIL can prevent breast cancerinduced bone destruction and highlight the potential of this ligand for the treatment of metastatic breast cancer in bone.

Enhanced Metastasis Suppression by Targeting TRAIL Receptor 2 in a Murine Model of Triple-Negative Breast Cancer

“…Although TRAIL and an agonistic TRAIL-R2 mAb (Apomab) were previously reported to inhibit bone metastases induced by intratibial injection of breast cancer cells (42,43), our findings are the first to show the antimetastatic activity of TRAIL receptor agonists in an orthotopic model of breast cancer that more faithfully recapitulates the entire metastatic cascade in vivo, including stromal invasion, intravasation, extravasation, and lung colonization. Moreover, our studies are the first direct comparison of the therapeutic efficacy of TRAIL-R1 and TRAIL-R2 agonists in a murine model of breast cancer.…”

Combined therapy with the RANKL inhibitor RANK-Fc and rhApo2L/TRAIL/dulanermin reduces bone lesions and skeletal tumor burden in a model of breast cancer skeletal metastasis

“…6), consistent with previous findings. 43 Since we also observed that rhApo2L/ TRAIL did not detectably reduce osteoclasts localized to the tumor/bone interface, the reduction in local osteolysis is presumably due to the local reduction in MDA-MB-231 tumor cells in the bone, which would subsequently attenuate the release of observed with either agent alone. We used multiple parameters to assess the efficacy of rhApo2L/TRAIL and RANK-Fc in our skeletal metastasis study, including measurement of tumor observed in the bone microenvironment and not observed in tumors implanted subcutaneously, which, along with the unique effect of RANKL inhibition to reduce osteoclastogenesis, supports the hypothesis that RANK-Fc is disrupting the vicious cycle as observed with previous studies using other RANKL inhibitors.…”

“…43,44 We have expanded those findings by demonstrating that rhApo2L/TRAIL combined with muRANK-Fc enhances the reduction in skeletal tumor burden burden by BLI, as well as histopathologic quantitation and X-ray radiography. Based on tumor histology and X-ray lesions (Fig.…”

Does Apo2L/TRAIL play any physiologic role in osteoclastogenesis?

“…5 We have shown that the version of Apo2L/TRAIL that is currently being used in phase 1b clinical trials, inhibited breast cancer growth within bone and protected against cancer-induced osteolysis in a murine model. 6 These results could be explained by the potential of Apo2L/TRAIL to either (1) directly induce apoptosis of breast cancer cells within the bone microenvironment, or, based on the above evidence, (2) block osteoclastogenesis or osteoclast activity via direct inhibitory effects. We have examined in detail the effect of the clinical grade recombinant Apo2L/ TRAIL on bone histology in mice, and also its effect on osteoclast differentiation and bone resorption in 3 independent in vitro models of osteoclastogenesis.…”