Integrative molecular analyses define correlates of high B7-H3 expression in metastatic castrate-resistant prostate cancer.
Integrative molecular analyses define correlates of high B7-H3 expression in metastatic castrate-resistant prostate cancer.
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DOI：
10.1038/s41698-022-00323-2
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发表时间：
2022-11-02
影响因子：
7.9
通讯作者：
Hwang, Justin
中科院分区：
文献类型：
--
作者：
Shi, Xiaolei;Day, Abderrahman;Bergom, Hannah E.;Tape, Sydney;Baca, Sylvan C.;Sychev, Zoi E.;Larson, Gabrianne;Bozicevich, Asha;Drake, Justin M.;Zorko, Nicholas;Wang, Jinhua;Ryan, Charles J.;Antonarakis, Emmanuel S.;Hwang, Justin
B7-H3（CD 276）是一种在前列腺癌中过表达的免疫检查点，在正常组织中表达最低，与预后不良相关，使其成为一种极好的治疗靶点。我们研究了转移性去势抵抗性前列腺癌（mCRPC）中B7-H3的表达及其调控。我们发现B7-H3转录物的表达高于其他免疫治疗靶点（CTLA-4，PD-L1/2），包括缺乏前列腺特异性膜抗原（PSMA）表达的肿瘤。Enzalutamide耐药mCRPC细胞显示B7-H3的量增加，这与耐药信号通路相关。使用机器学习算法，B7-H3的基因网络与雄激素受体（AR）和AR辅因子（HOXB 13，FOXA 1）网络密切相关。在mCRPC样本中，B7-H3启动子和远端增强子区域表现出增强的转录活性，并与AR及其辅因子直接结合。总之，我们的研究表征了表达B7-H3的mCRPC肿瘤的分子特征和表观遗传调控，这为mCRPC患者提供了最佳的精确肿瘤学方法。
B7-H3 (CD276) is an immune checkpoint overexpressed in prostate cancer with minimal expression in normal tissues and associated with poor prognosis, making it an excellent therapy target. We interrogated B7-H3 expression and its regulation in metastatic castration-resistant prostate cancer (mCRPC). We found greater expression of B7-H3 transcript relative to other immunotherapy targets (CTLA-4, PD-L1/2), including in tumors that lacked expression of prostate-specific membrane antigen (PSMA). Enzalutamide-resistant mCRPC cells demonstrated increased amounts of B7-H3, and this was associated with resistance signaling pathways. Using a machine-learning algorithm, the gene network of B7-H3 was strongly correlated with androgen receptor (AR) and AR co-factor (HOXB13, FOXA1) networks. In mCRPC samples, the B7-H3 promoter and distal enhancer regions exhibited enhanced transcriptional activity and were directly bound by AR and its co-factors. Altogether, our study characterizes molecular profiles and epigenetic regulation of B7-H3-expressing mCRPC tumors, which informs optimal precision-oncology approaches for mCRPC patients.
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影响因子：
5.8
作者：
Liberzon, Arthur;Subramanian, Aravind;Mesirov, Jill P.
通讯作者：
Mesirov, Jill P.
影响因子：
50.3
作者：
Taylor BS;Schultz N;Hieronymus H;Gopalan A;Xiao Y;Carver BS;Arora VK;Kaushik P;Cerami E;Reva B;Antipin Y;Mitsiades N;Landers T;Dolgalev I;Major JE;Wilson M;Socci ND;Lash AE;Heguy A;Eastham JA;Scher HI;Reuter VE;Scardino PT;Sander C;Sawyers CL;Gerald WL
通讯作者：
Gerald WL
DOI：
10.1002/pros.23313
发表时间：
2017-05
期刊：
The Prostate
影响因子：
--
作者：
Nguyen HM;Vessella RL;Morrissey C;Brown LG;Coleman IM;Higano CS;Mostaghel EA;Zhang X;True LD;Lam HM;Roudier M;Lange PH;Nelson PS;Corey E
通讯作者：
Corey E
DOI：
10.2967/jnumed.120.260455
发表时间：
2021-03
期刊：
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
影响因子：
--
作者：
Carlucci G;Ippisch R;Slavik R;Mishoe A;Blecha J;Zhu S
通讯作者：
Zhu S
DOI：
10.1056/nejmoa1315815
发表时间：
2014-09-11
期刊：
The New England journal of medicine
影响因子：
--
作者：
Antonarakis ES;Lu C;Wang H;Luber B;Nakazawa M;Roeser JC;Chen Y;Mohammad TA;Chen Y;Fedor HL;Lotan TL;Zheng Q;De Marzo AM;Isaacs JT;Isaacs WB;Nadal R;Paller CJ;Denmeade SR;Carducci MA;Eisenberger MA;Luo J
通讯作者：
Luo J