Abstract
Urokinase plasminogen activator receptor (uPAR) is implicated in tumor growth and metastasis due to its ability to activate latent growth factors, proteases, and different oncogenic signaling pathways upon binding to different ligands. Elevated uPAR expression is correlated with the increased aggressiveness of cancer cells, which led to its credentialing as an attractive diagnostic and therapeutic target in advanced solid cancer. Here, we examine the antitumor effects of a humanized anti-uPAR antibody (huATN-658) alone and in combination with the approved bisphosphonate Zometa (Zoledronic acid) on skeletal lesion through a series of studies in vitro and in vivo. Treatment with huATN-658 or Zometa alone significantly decreased human MDA-MB-231 cell proliferation and invasion in vitro, effects which were more pronounced when huATN-658 was combined with Zometa. In vivo studies demonstrated that huATN-658 treatment significantly reduced MDA-MB-231 primary tumor growth compared with controls. In a model of breast tumor-induced bone disease, huATN-658 and Zometa were equally effective in reducing skeletal lesions. The skeletal lesions were significantly reduced in animals receiving the combination of huATN-658 + Zometa compared with monotherapy treatment. These effects were due to a significant decrease in osteoclastic activity and tumor cell proliferation in the combination treatment group. Transcriptome analysis revealed that combination treatment significantly changes the expression of genes from signaling pathways implicated in tumor progression and bone remodeling. Results from these studies provide a rationale for the continued development of huATN-658 as a monotherapy and in combination with currently approved agents such as Zometa in patients with metastatic breast cancer.
Highlights
Despite the advances made in the field of cancer therapeutics, treatment of metastatic disease remains a challenge and accounts for more than 90% of the breast cancer-related deaths worldwide.[1]
In order to improve patient outcome and quality of life (QOL) for survivors, there is an urgent need for the development and validation of rational and effective anticancer therapeutic strategies that can be effective in reducing breast tumor growth in nonskeletal and skeletal sites
Targeting of Urokinase plasminogen activator receptor (uPAR) in general and by the clinical candidate huATN-658 has shown significant anticancer effects in a number of preclinical studies[22,23]; Using huATN-658, we assessed the therapeutic potential for targeting breast cancer and for the first time, breast tumor-induced bone disease
Summary
Targeting of uPAR in general and by the clinical candidate huATN-658 has shown significant anticancer effects in a number of preclinical studies[22,23]; Using huATN-658, we assessed the therapeutic potential for targeting breast cancer and for the first time, breast tumor-induced bone disease. The RNA-Seq results showed that the huATN-658 + Zometa combination treatment significantly increases the expression of COL1A2 and SPOCK3 genes encoding for type 1 collagen and osteonectin proteins These proteins are implicated in bone remodeling.[41] The intratibial model used in this study may not be ideal for studying skeletal metastasis; it adequately assesses tumor cells colonization and growth in the skeleton and may not fully assess the antimetastatic potential. Primary mammary tumor growth and skeletal lesion following mammary fat pad and intratibial inoculation, the magnitude of the anticancer effects seen in vitro was lower than that seen in vivo These findings are consistent with previous studies in prostate and colorectal cancer.[22,42] This discrepancy can be attributed to the 1833 cells were plated onto each well of six-well plates and treated with IgG control (50 μg·mL−1), huATN-658 (50 μg·mL−1), Zometa (10 μmol·L−1), and huATN-658 + Zometa for 2 days (48 h). For the intratibial model of breast cancer, 2 × 105 MDA-MB-231 or 5 × 104 MDA-
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