Dickkopf-1 Can Lead to Immune Evasion in Metastatic Castration-Resistant Prostate Cancer.

Autor:	Wise DR; Department of Medicine, Perlmutter Cancer Center, NYU Langone Medical Center, New York, NY., Schneider JA; Department of Urology, NYU Langone Medical Center, New York, NY., Armenia J; Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY., Febles VA; Department of Medicine, Perlmutter Cancer Center, NYU Langone Medical Center, New York, NY., McLaughlin B; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY., Brennan R; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY., Thoren KL; Department of Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY., Abida W; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY., Sfanos KS; Sidney Kimmel Comprehensive Cancer Center, School of Medicine, Johns Hopkins University, Baltimore, MD.; Department of Pathology, School of Medicine, Johns Hopkins University, Baltimore, MD.; Brady Urological Institute, School of Medicine, Johns Hopkins University, Baltimore, MD., De Marzo AM; Sidney Kimmel Comprehensive Cancer Center, School of Medicine, Johns Hopkins University, Baltimore, MD.; Department of Pathology, School of Medicine, Johns Hopkins University, Baltimore, MD.; Brady Urological Institute, School of Medicine, Johns Hopkins University, Baltimore, MD., Yegnasubramanian S; Sidney Kimmel Comprehensive Cancer Center, School of Medicine, Johns Hopkins University, Baltimore, MD.; Department of Pathology, School of Medicine, Johns Hopkins University, Baltimore, MD., Fox JJ; Molecular Imaging and Therapy Service, Memorial Sloan Kettering Cancer Center, New York, NY., Haas M; Leap Therapeutics, Cambridge, MA., Heath H; Leap Therapeutics, Cambridge, MA., Kagey MH; Leap Therapeutics, Cambridge, MA., Newman W; Leap Therapeutics, Cambridge, MA., Sirard CA; Leap Therapeutics, Cambridge, MA., Fleisher M; Department of Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY., Morris MJ; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY., Chen Y; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY., Larson SM; Molecular Imaging and Therapy Service, Memorial Sloan Kettering Cancer Center, New York, NY., Haffner MC; Sidney Kimmel Comprehensive Cancer Center, School of Medicine, Johns Hopkins University, Baltimore, MD.; Department of Pathology, School of Medicine, Johns Hopkins University, Baltimore, MD., Nelson PS; Departments of Medicine and Pathology, University of Washington, and Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA., Schultz N; Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY., Garabedian MJ; Department of Urology, NYU Langone Medical Center, New York, NY.; Department of Microbiology, NYU Langone Medical Center, New York, NY., Scher HI; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY., Logan SK; Department of Urology, NYU Langone Medical Center, New York, NY., Sawyers CL; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY.; Howard Hughes Medical Institute, Memorial Sloan Kettering Cancer Center, New York, NY.
Jazyk:	angličtina
Zdroj:	JCO precision oncology [JCO Precis Oncol] 2020 Sep 29; Vol. 4. Date of Electronic Publication: 2020 Sep 29 (Print Publication: 2020).
DOI:	10.1200/PO.20.00097
Abstrakt:	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). Competing Interests: The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center. Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments). David R. WiseHonoraria: OncLive Consulting or Advisory Role: Best Doctors, Leap Therapeutics, GLG, Guidepoint Global, Pfizer, Foundation Medicine, Silverlight, Alphasights Travel, Accommodations, Expenses: PfizerJeffrey A. SchneiderStock and Other Ownership Interests: Abbott Laboratories, AstraZeneca, AbbVie, CVS Health, MerckBrigit McLaughlinEmployment: Bristol Myers Squibb Stock and Other Ownership Interests: Bristol Myers SquibbRyan BrennanEmployment: Flatiron Health Stock and Other Ownership Interests: RocheKatie L. ThorenResearch Funding: Sebia (Inst), The Binding Site (Inst)Wassim AbidaHonoraria: CARET Consulting or Advisory Role: Clovis Oncology, Janssen Pharmaceuticals, MORE Health, ORIC Pharmaceuticals, Daiichi Sankyo Research Funding: AstraZeneca (Inst), Zenith Epigenetics (Inst), Clovis Oncology (Inst), GlaxoSmithKline (Inst) Travel, Accommodations, Expenses: GlaxoSmithKline, Clovis Oncology, ORIC PharmaceuticalsAngelo M. De MarzoConsulting or Advisory Role: Cepheid Research Funding: Janssen Research & DevelopmentSrinivasan YegnasubramanianStock and Other Ownership Interests: Brahm Astra Therapeutics, Digital Harmonic Consulting or Advisory Role: Cepheid Research Funding: Cepheid (Inst), Celgene (Inst), Bristol Myers Squibb (Inst), Janssen Pharmaceuticals (Inst) Patents, Royalties, Other Intellectual Property: Patent: “COMPARE-MS: A novel technique for rapid, sensitive, and accurate detection of DNA methylation”; Patent: “Agents for reversing epigenetic silencing of genes”; Patent: “DNA methylation markers for metastatic prostate cancer”; Patent pending: “Induction of synthetic lethality with epigenetic therapy”; Patent: “Bisulfite-converted duplexes for the strand-specific detection and quantification of rare mutations”Michael HaasEmployment: Leap Therapeutics Stock and Other Ownership Interests: Leap Therapeutics Research Funding: Leap TherapeuticsMichael H. KageyEmployment: Leap Therapeutics, Biogen (I) Stock and Other Ownership Interests: Syros Pharmaceuticals Consulting or Advisory Role: Medical Research Commercialisation Fund Patents, Royalties, Other Intellectual Property: Patents pending and granted for discovery-based work at Leap Therapeutics (current employer), Tensha Therapeutics (acquired by Roche), and the Whitehead Institute (licensed to Syros Pharmaceuticals)Walter NewmanEmployment: Leap Therapeutics Leadership: Leap Therapeutics Stock and Other Ownership Interests: Leap Therapeutics Patents, Royalties, Other Intellectual Property: May be a co-patentee on Leap Therapeutics intellectual propertyCynthia A. SirardEmployment: Leap Therapeutics Leadership: Leap Therapeutics Stock and Other Ownership Interests: Leap Therapeutics Patents, Royalties, Other Intellectual Property: Pending patent application No. 62/260,959 Travel, Accommodations, Expenses: Leap TherapeuticsMichael J. MorrisConsulting or Advisory Role: Astellas Pharma, Bayer AG, Endocyte, Advanced Accelerator Applications, Blue Earth Diagnostics, Tokai Pharmaceuticals, Tolmar Pharmaceuticals, ORIC Pharmaceuticals Research Funding: Bayer AG (Inst), Sanofi (Inst), Endocyte (Inst), Progenics (Inst), Corcept Therapeutics (Inst), Roche (Inst), Genentech (Inst) Travel, Accommodations, Expenses: Bayer AG, EndocyteYu ChenStock and Other Ownership Interests: ORIC Pharmaceuticals Honoraria: Merck Patents, Royalties, Other Intellectual Property: Invention related to glucocorticoid inhibitors for treatment of prostate cancer (SK2013-045)Steven M. LarsonStock and Other Ownership Interests: Ymabs Therapeutics, Elucida Consulting or Advisory Role: Prescient Therapeutics Research Funding: Wilex, Regeneron Pharmaceuticals, Ymabs Therapeutics Patents, Royalties, Other Intellectual Property: Synthesis and utilization of 17-methyl and 17-cyclo-propylmethyl-3, 14-di-hydroxy-4, 5-epoxy 6 b-fluoromorphines (foxy and cyclofoxy) as (18F)-labeled opiate ligands for positron emission transaxial tomography (Rice KC, Pert CB, Burke TR Jr, Larson SM, Eckelman WC, Channing MA; October 4, 1988; US Patent No. 4,775,759); Antigen-specific composition and in vivo methods for detecting and localizing an antigenic site and for radiotherapy (Larson SM, Finn R, Carrasquillo JA, Reynolds JC, Neumann RD, Graham MC, Pentlow KS; February 9, 1993; US Patent No. 5,185,142); Non-invasive imaging and quantification of specific antigen and uses thereof (Smith-Jones P, Larson SM; January 6, 2003; Provisional Patent Application Registration No. 28,325); Single chain Fv polynucleotide or peptide construct of anti-ganglioside GD2 antibodies, cells expressing same and related methods (Cheung NK, Larson SM, Guo HF, Rivlin K, Sadelain M; US Patent No. 6,451,995); Small-molecule HSP90 inhibitors, chiosis, gabriela (Huazhong H, Llauger-Bufi L, Joungnam K, Larson S, Smith-Jones P; November 16, 2010, US Patent No. 7,834,181); Multi-specific antibodies with affinity for human A33 antigen and DOTA metal complex and uses thereof (Cheal S, Hong X, Larson SM, Cheung NK; February 9, 2015; US Patent No. 62,113,988); Systems and methods for determining optimum patient-specific antibody dose for tumor targeting (Zanzonico P, Cheal SM, Larson SM, Osborne J, Fung Edward K; May 22, 2015, US Patent No. 62,165699)Peter S. NelsonConsulting or Advisory Role: Janssen Oncology, Astellas Pharma, Roche, Genentech, Bristol Myers Squibb Research Funding: Genomic Health (Inst), Expert Testimony: Veneble-Fitzpatrick Law Firm Travel, Accommodations, Expenses: Janssen OncologyHoward I. ScherLeadership: Asterias Biotherapeutics Stock and Other Ownership Interests: Asterias Biotherapeutics Honoraria: Research to Practice Consulting or Advisory Role: Janssen Biotech, Amgen, Janssen Research & Development, Menarini Silicon Biosystems, WIRB-Copernicus Group, ESSA, Sanofi, Ambry Genetics, Konica Minolta, Pfizer, Bayer AG Research Funding: Janssen Pharmaceuticals (Inst), Illumina (Inst), Epic Sciences (Inst), Menarini Silicon Biosystems (Inst), Thermo Fisher Scientific (Inst) Travel, Accommodations, Expenses: Asterias Biotherapeutics, Menarini Silicon Biosystems, Amgen, WIRB-Copernicus Group, Konica Minolta, ESSA, Prostate Cancer Foundation, Sanofi, Bayer AG, Phosplatin TherapeuticsCharles L. SawyersLeadership: Novartis Stock and Other Ownership Interests: Novartis, Agios, Blueprint Medicines, BeiGene, ORIC Pharmaceuticals, Foghorn, PMV Pharma, KSQ Therapeutics, Petra Pharma Consulting or Advisory Role: Novartis, Blueprint Medicines, Agios, BeiGene, ORIC Pharmaceuticals, Foghorn, PMV Pharma, KSQ Therapeutics, Petra Pharma, Arsenal, Housey Pharmaceuticals Patents, Royalties, Other Intellectual Property: Xtandi, Apalutamide No other potential conflicts of interest were reported. (© 2020 by American Society of Clinical Oncology.)
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