Abstract 3794: Inhibition of prostate cancer bone metastases by the dickkopf-1 neutralizing antibody BHQ880

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Abstract Advanced prostate carcinoma (PCa) is usually complicated by the presence of bone metastases. Current therapies targeting bone metastases are suboptimal as the metastases progress in spite of therapy. Accordingly, novel therapeutics are needed to target these lesions. The Wnt inhibitor Dickkopf-1 (DKK-1) appears to play an important role in progression of PCa bone metastases. Overexpression of DKK-1 by PCa promotes tumor growth and bone lysis in laboratory studies and DKK1 is present in clinical PCa bone metastases. Development of a fully humanized anti-DKK-1 neutralizing antibody, BHQ880 (Novartis), provides a potential therapeutic strategy to target PCa bone metastases. The goal of this study was to test if BHQ880 could impact PCa bone metastases. PC-3-luc cells (2.5x105) were injected intratibially into mice. Treatment with anti-DKK-1 or isotype control antibody (n=12 mice per group) was initiated 0, 7, or 14 days post-tumor injection. Mice were treated three times weekly by intraperitoneal injection with 200 μg/mouse (approximately 10 mg/kg) Tumor growth and bone lysis were assessed by weekly bioluminescence and bi-weekly radiography, respectively. All mice were euthanized 31 days post-tumor injection, tumor bearing limbs were formalin fixed and serum was obtained. Tumor bearing limbs were analyzed by dual energy x-ray absorptiometry (DEXA) and histology. Serum was assayed for the bone turnover biomarkers alkaline phosphatase (ALP), osteocalcin (OC), and tartate-resistant acid phosphatase 5b (TRAP5b). BHQ880 was well tolerated with no significant side effects observed. Significant inhibition of tumor growth was observed in mice where treatment was initiated 7 or 14 days post-tumor challenge when established tumors were present. Two mice from the 14-day treatment group had tumor regressions after treatment with BHQ880. Treatment with BHQ880 resulted in decreased bone lysis as determined using DEXA. Furthermore, increased serum concentrations of ALP and OC in mice treated with BHQ880 suggest increased bone production; no significant difference in TRAP5b concentration between treated and untreated mice was found. Treatment with the DKK-1 neutralizing antibody BHQ880 was found to inhibit tumor growth, tumor-induced osteolysis and increase serum bone remodeling markers associated with increased bone production in a murine model of PCa bone metastasis. These data suggest that anti-DKK-1 treatment is a plausible mechanism for inhibition of progression of PCa bone metastases. These data suggest that inhibition of DKK-1 may be an effective strategy to inhibit PCa growth in bone. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3794. doi:1538-7445.AM2012-3794