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Antisense mediated blockade of Dickkopf 1 attenuates tumor survival, metastases and bone damage in experimental
Andrew Haskell1, Simin Pan1, Robert Reese2
1Department of Medical Physiology, Texas A&M College of Medicine, Bryan, TX, 77807, USA.
Abstract:
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.
Insights
Targeting Dickkopf-1 (Dkk-1) with DkkMo therapy shows promise for osteosarcoma (OS). This approach inhibits tumor growth, survival, and metastasis while preserving bone in preclinical models.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Osteosarcoma (OS) is the most common primary bone cancer.
- Dickkopf-1 (Dkk-1), a Wnt inhibitor, is linked to OS bone destruction, survival, and metastasis.
Purpose of the Study:
- To investigate Dkk-1's role in OS progression.
- To explore therapeutic strategies targeting Dkk-1 activity.
Main Methods:
- Examined Dkk-1's role in OS disease progression.
- Utilized a Dkk-1 targeting morpholino (DkkMo) in vitro and in vivo.
- Assessed DkkMo effects on OS survival, osteogenic activity, tumor growth, necrosis, metastasis, and bone preservation in a patient-derived xenograft (PDX) model.
Main Results:
- Dkk-1 promotes OS survival via a non-canonical Wnt pathway upregulating aldehyde dehydrogenase 1A1.
- DkkMo reduced OS survival and enhanced osteogenic activity in vitro.
- DkkMo treatment slowed tumor expansion, increased necrosis, inhibited metastasis, and preserved bone in an OS PDX model.
- DkkMo reduced tumor cell proliferation and inflammatory cell infiltration, while reinitiating osteogenic phenotypes.
Conclusions:
- DkkMo effectively targets osteosarcoma growth, survival, and metastasis.
- DkkMo demonstrates potential for preserving bone integrity in OS.
- DkkMo represents a promising therapeutic strategy for osteosarcoma treatment.
