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Updated: Dec 6, 2025
A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
Published on: March 6, 2018
Dickkopf-1 Can Lead to Immune Evasion in Metastatic Castration-Resistant Prostate Cancer
David R Wise1, Jeffrey A Schneider2, Joshua Armenia3
1Department of Medicine, Perlmutter Cancer Center, NYU Langone Medical Center, New York, NY.
Purpose:
Metastatic castration-resistant prostate cancer (mCRPC) with low androgen receptor (AR) and without neuroendocrine signaling, termed double-negative prostate cancer (DNPC), is increasingly prevalent in patients treated with AR signaling inhibitors and is in need of new biomarkers and therapeutic targets.
Methods:
Candidate genes enriched in DNPC were determined using differential gene expression analysis of discovery and validation cohorts of mCRPC biopsies. Laboratory studies were carried out in human mCRPC organoid cultures, prostate cancer (PCa) cell lines, and mouse xenograft models. Epigenetic studies were carried out in a rapid autopsy cohort.
Results:
Dickkopf-1 (DKK1) expression is increased in DNPC relative to prostate-specific antigen (PSA)-expressing mCRPC in the Stand Up to Cancer/Prostate Cancer Foundation discovery cohort (11.2 v 0.28 reads per kilobase per million mapped reads; q < 0.05; n = 117) and in the University of Washington/Fred Hutchinson Cancer Research Center cohort (9.2 v 0.99 fragments per kilobase of transcript per million mapped reads; P < .0001). DKK1 expression can be regulated by activated Wnt signaling in vitro and correlates with activating canonical Wnt signaling mutations and low PSA mRNA in mCRPC biopsies (P < .05). DKK1 hypomethylation was associated with increased DKK1 mRNA expression (Pearson r = -0.66; P < .0001) in a rapid autopsy cohort (n = 7). DKK1-high mCRPC biopsies are infiltrated with significantly higher numbers of quiescent natural killer (NK) cells (P < .005) and lower numbers of activated NK cells (P < .0005). Growth inhibition of the human PCa model PC3 by the anti-DKK1 monoclonal antibody DKN-01 depends on the presence of NK cells in a severe combined immunodeficient xenograft mouse model.
Conclusion:
These results support DKK1 as a contributor to the immunosuppressive tumor microenvironment of DNPC. These data have provided the rationale for a clinical trial targeting DKK1 in mCRPC (ClinicalTrials.gov identifier: NCT03837353).
Insights
Dickkopf-1 (DKK1) is elevated in double-negative prostate cancer (DNPC), contributing to an immunosuppressive tumor microenvironment. Targeting DKK1 shows promise for treating metastatic castration-resistant prostate cancer (mCRPC).
Area of Science:
- Oncology
- Cancer Biology
- Immunology
Background:
- Metastatic castration-resistant prostate cancer (mCRPC) with double-negative prostate cancer (DNPC) is an emerging clinical challenge.
- DNPC is characterized by low androgen receptor (AR) signaling and absence of neuroendocrine differentiation.
- New biomarkers and therapeutic targets are urgently needed for DNPC.
Purpose of the Study:
- To identify novel therapeutic targets and biomarkers for DNPC.
- To investigate the role of Dickkopf-1 (DKK1) in DNPC pathogenesis and the tumor microenvironment.
Main Methods:
- Differential gene expression analysis of mCRPC patient biopsies.
- In vitro studies using human mCRPC organoid cultures and cell lines.
- In vivo studies using mouse xenograft models and epigenetic analysis of autopsy samples.
Main Results:
- DKK1 expression is significantly increased in DNPC compared to other mCRPC subtypes.
- DKK1 expression is regulated by Wnt signaling and associated with hypomethylation of the DKK1 gene.
- DKK1-high tumors exhibit an immunosuppressive microenvironment with increased quiescent natural killer (NK) cells and reduced activated NK cells.
- Anti-DKK1 antibody DKN-01 efficacy in preclinical models depends on NK cell presence.
Conclusions:
- DKK1 contributes to the immunosuppressive tumor microenvironment in DNPC.
- DKK1 is a potential therapeutic target for mCRPC.
- Clinical trials targeting DKK1 in mCRPC are warranted and underway.
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