David R Wise1, Jeffrey A Schneider2, Joshua Armenia3, Victor Adorno Febles1, Bridget McLaughlin4, Ryan Brennan4, Katie L Thoren5, Wassim Abida4, Karen S Sfanos6,7,8, Angelo M De Marzo6,7,8, Srinivasan Yegnasubramanian6,7, Josef J Fox9, Michael Haas10, Heidi Heath10, Michael H Kagey10, Walter Newman10, Cynthia A Sirard10, Martin Fleisher5, Michael J Morris4, Yu Chen4,11, Steven M Larson9, Michael C Haffner6,7, Peter S Nelson12, Nikolaus Schultz3, Michael J Garabedian2,13, Howard I Scher4, Susan K Logan2, Charles L Sawyers11,14. 1. Department of Medicine, Perlmutter Cancer Center, NYU Langone Medical Center, New York, NY. 2. Department of Urology, NYU Langone Medical Center, New York, NY. 3. Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY. 4. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY. 5. Department of Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY. 6. Sidney Kimmel Comprehensive Cancer Center, School of Medicine, Johns Hopkins University, Baltimore, MD. 7. Department of Pathology, School of Medicine, Johns Hopkins University, Baltimore, MD. 8. Brady Urological Institute, School of Medicine, Johns Hopkins University, Baltimore, MD. 9. Molecular Imaging and Therapy Service, Memorial Sloan Kettering Cancer Center, New York, NY. 10. Leap Therapeutics, Cambridge, MA. 11. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY. 12. Departments of Medicine and Pathology, University of Washington, and Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA. 13. Department of Microbiology, NYU Langone Medical Center, New York, NY. 14. Howard Hughes Medical Institute, Memorial Sloan Kettering Cancer Center, New York, NY.
Abstract
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).
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).
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