Wise David R, Schneider Jeffrey A, Armenia Joshua, Febles Victor Adorno, McLaughlin Bridget, Brennan Ryan, Thoren Katie L, Abida Wassim, Sfanos Karen S, De Marzo Angelo M, Yegnasubramanian Srinivasan, Fox Josef J, Haas Michael, Heath Heidi, Kagey Michael H, Newman Walter, Sirard Cynthia A, Fleisher Martin, Morris Michael J, Chen Yu, Larson Steven M, Haffner Michael C, Nelson Peter S, Schultz Nikolaus, Garabedian Michael J, Scher Howard I, Logan Susan K, Sawyers Charles L
Department of Medicine, Perlmutter Cancer Center, NYU Langone Medical Center, New York, NY.
Department of Urology, NYU Langone Medical Center, New York, NY.
JCO Precis Oncol. 2020 Sep 29;4. doi: 10.1200/PO.20.00097. eCollection 2020.
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.
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.
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 0.28 reads per kilobase per million mapped reads; < 0.05; n = 117) and in the University of Washington/Fred Hutchinson Cancer Research Center cohort (9.2 0.99 fragments per kilobase of transcript per million mapped reads; < .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 ( < .05). hypomethylation was associated with increased DKK1 mRNA expression (Pearson = -0.66; < .0001) in a rapid autopsy cohort (n = 7). DKK1-high mCRPC biopsies are infiltrated with significantly higher numbers of quiescent natural killer (NK) cells ( < .005) and lower numbers of activated NK cells ( < .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.
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).
转移性去势抵抗性前列腺癌（mCRPC）中雄激素受体（AR）水平低且无神经内分泌信号，称为双阴性前列腺癌（DNPC），在接受AR信号抑制剂治疗的患者中越来越普遍，需要新的生物标志物和治疗靶点。
使用mCRPC活检的发现队列和验证队列的差异基因表达分析来确定在DNPC中富集的候选基因。在人mCRPC类器官培养物、前列腺癌（PCa）细胞系和小鼠异种移植模型中进行实验室研究。在快速尸检队列中进行表观遗传学研究。
在“勇敢对抗癌症/前列腺癌基金会”发现队列中，与表达前列腺特异性抗原（PSA）的mCRPC相比，Dickkopf-1（DKK1）在DNPC中的表达增加（每千碱基每百万映射 reads 中为11.2 ± 0.28 reads；P < 0.05；n = 117），在华盛顿大学/弗雷德·哈钦森癌症研究中心队列中也是如此（每千碱基转录本每百万映射 reads 中为9.2 ± 0.99片段；P <.0001）。DKK1表达在体外可由激活的Wnt信号调节，并且与mCRPC活检中激活的经典Wnt信号突变和低PSA mRNA相关（P <.05）。在快速尸检队列（n = 7）中，低甲基化与DKK1 mRNA表达增加相关（Pearson r = -0.66；P <.0001）。DKK1高表达的mCRPC活检中浸润的静止自然杀伤（NK）细胞数量明显更多（P <.005），而活化NK细胞数量更少（P <.0005）。在严重联合免疫缺陷异种移植小鼠模型中，抗DKK1单克隆抗体DKN-01对人PCa模型PC3的生长抑制取决于NK细胞的存在。
这些结果支持DKK1是DNPC免疫抑制肿瘤微环境的一个促成因素。这些数据为在mCRPC中靶向DKK1的临床试验提供了理论依据（ClinicalTrials.gov标识符：NCT03837353）。
