Antisense mediated blockade of Dickkopf 1 attenuates tumor survival, metastases and bone damage in experimental osteosarcoma

Osteosarcoma (OS) is the most common primary bone malignancy. The canonical Wnt inhibitor Dickkopf-1 (Dkk-1) has been implicated in bone destruction, tumor survival and metastases during OS. We examined the role of Dkk-1 in OS disease progression and explored strategies for targeting its activity. Dkk-1 enhances OS survival by amplifying a non-canonical Wnt pathway that upregulates aldehyde dehydrogenase 1A1. Targeting of Dkk-1 transcription with a vivo morpholino (DkkMo) reduced OS survival and enhanced osteogenic activity of OS in vitro. DkkMo as a single agent slowed tumor expansion, increased tumor necrosis, inhibited metastases and preserved bone in a PDX model of OS. DkkMo also reduced the frequency of dividing tumor cells and reinitiated a regenerative osteogenic phenotype in tumors and stroma while reducing infiltration of inflammatory cells. These findings indicate that DkkMo has the potential to safely target osteosarcoma growth, survival, metastases and bone destruction.