A monoclonal antibody against the Wnt signaling inhibitor dickkopf-1 inhibits osteosarcoma metastasis in a preclinical model

Abstract

The outcome of patients with metastatic osteosarcoma has not improved since the introduction of chemotherapy in the 1970s. Development of therapies targeting the metastatic cascade is a tremendous unmet medical need. The Wnt signaling pathway has been the focus of intense investigation in osteosarcoma because of its role in normal bone development. Although the role of Wnt signaling in the pathogenesis of osteosarcoma is controversial, there are several reports of dickkopf-1 (DKK-1), a Wnt signaling antagonist, possibly playing a pro-tumorigenic role. In this work we investigated the effect of anti-DKK-1 antibodies on the growth and metastasis of patient-derived osteosarcoma xenografts. We were able to detect human DKK-1 in the blood of tumor-bearing mice and found a correlation between DKK-1 level and tumor proliferation. Treatment with the anti-DKK-1 antibody, BHQ880, slowed the growth of orthotopically implanted patient-derived osteosarcoma xenografts and inhibited metastasis. This effect was correlated with increased nuclear beta-catenin staining and increased expression of the bone differentiation marker osteopontin. These findings suggest that Wnt signaling is anti-tumorigenic in osteosarcoma, and support the targeting of DKK-1 as an anti-metastatic strategy for patients with osteosarcoma.

Rationale for targeting the Wnt signalling modulator Dickkopf‐1 for oncology

“…In support of this, knockdown of DKK1 decreased tumour growth and angiogenesis in hepatocellular carcinoma (Huang et al , ). In addition to affecting primary tumour growth, DKK1 has also been linked to the development of metastasis in bone, breast, liver, lung and prostate cancer models, possibly related to the prominent role of DKK1 in stimulating migration and invasion observed in vitro (Thudi et al , ; Tao et al , ; Huang et al , ; Goldstein et al , ; Malladi et al , ; Pang et al , ). Taken together, these data demonstrate that DKK1 has tumour‐promoting activity in animal models via effects on tumour growth, metastasis and angiogenesis.…”

Membrane‐bound Dickkopf‐1 in Foxp3+ regulatory T cells suppresses T‐cell‐mediated autoimmune colitis

“…Mice that were homozygous for the total Dkk1 knockout died at birth due to defects in the cranium and structures formed by the neural crest . Several studies have reported that elevated levels of DKK‐1 were associated with disease severity or a poor prognosis, which provided a rationale to regulate the canonical Wnt pathway in cancer and bone diseases for therapeutic purposes . It has been shown that DKK‐1 might also use cell‐to‐cell contact to bind to LRP‐6 …”

Tumor‐adjacent tissue co‐expression profile analysis reveals pro‐oncogenic ribosomal gene signature for prognosis of resectable hepatocellular carcinoma

“…; see the Supporting information: Image based analysis of immunochemistry slides). Because DKK1 has been demonstrated to be a pathologically essential and strong prognostic factor in several studies, including ours, DKK1 could be a potential candidate for a future preclinical study of anti‐ DKK1 therapy in HCC, as described for myeloma (Fulciniti et al ., ) and osteosarcoma (Goldstein et al ., ).…”