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浙江大学学报（医学版）
浙江大学学报（医学版）  2016, Vol. 45 Issue (1): 91-97    DOI: 10.3785/j.issn.1008-9292.2016.01.15
综述     
转移性肾细胞癌靶向治疗的分子生物学基础
来翀1, 滕晓东2
1. 浙江大学医学院附属第一医院泌尿外科, 浙江 杭州 310003;
2. 浙江大学医学院附属第一医院病理科, 浙江 杭州 310003
Molecular biological foundation of targeted therapy for metastatic renal cell carcinoma
LAI Chong1, TENG Xiaodong2
1. Department of Urology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China;
2. Department of Pathology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
全文: PDF(914 KB)  
摘要: 

肾细胞癌发病率呈上升趋势,仅部分早期肾细胞癌患者可通过手术而治愈。如何在外科术后对患者进行更精准的抗肿瘤治疗是未来肾细胞癌治疗探索的方向。肾细胞癌中大部分转移性肾细胞癌为肾透明细胞癌,因此针对肾透明细胞癌最具有开发靶向药物的价值。目前靶点基因分子改变明确且具有临床应用价值的仍只有肾透明细胞癌特异性的VHL相关通路的关键蛋白。VHL的失活引起诸多基因的改变。临床现有的进展期肾透明细胞癌的靶向治疗大多数针对信号通路靶点,其他如程序性死亡蛋白1、抗体药物偶联物药物和干细胞则是针对新抗癌机制。尚无确切的能使大多数肾细胞癌患者受益且在临床广泛应用的治疗方案。本文结合临床经验和文献,对肾透明细胞癌的分子特征、VHL突变通路以及进展期肾透明细胞癌的靶向药物治疗现状和展望进行重点阐述,旨在寻找精确的肾细胞癌治疗靶点,指导临床肾细胞癌的精准化治疗。
关键词 ： 肾细胞癌,  转移性肾细胞癌,  肾透明细胞癌,  肾癌/精准治疗,  肾癌/靶向治疗,  综述    
Abstract：

The incidence of renal cell carcinoma (RCC) is increasing. Radical cure by surgery can only be achieved in patients with early stage tumors. How to precisely use antineoplastic agents after surgery is an important problem to be solved. Most metastatic RCCs are pathologically identified as clear cell RCC (ccRCC), thus to develop agents targeting ccRCC is critical. Most clinically available targeted therapies are based on targeting some spots in specific pathways; or based on targeting new anti-tumor mechanisms, such as programmed death-1(PD-1), antibody-drug conjugates (ADC) and stem cells. There is still no targeted therapy having definite effect to most RCC patients. Only von Hippel-Lindau (VHL) pathway so far has been confirmed to be related to ccRCC development and progression; the inactivation of VHL gene causes many significant downstream gene changes. The key proteins involved in VHL pathway may be potential therapeutic targets for ccRCC. In this article, we review the current progress of targeted therapy for RCC, focus on the molecular characteristics of ccRCC, its relation to VHL pathway, the potential therapeutic targets and future clinical application for metastatic ccRCC.
Key words： Renal cell carcinoma    Metastatic renal cell carcinoma    Clear cell renal cell carcinoma    Renal carcinoma/precision treatment    Renal carcinoma/targeted therapy    Review
收稿日期: 2015-08-25      出版日期: 2015-12-12
CLC:  R73  
基金资助:

浙江省公益技术应用研究计划(2016C33065)
通讯作者: 滕晓东(1964-),男,硕士,主任医师,主要从事临床病理诊断研究;E-mail:teng1723@163.com;http://orcid.org/0000-0003-3717-3370     E-mail: teng1723@163.com
作者简介: 来翀(1988-),女,博士,主治医师,主要从事肾癌发生发展及肾癌复发转移相关的分子病理学及临床应用研究;E-mail:clai8827@zju.edu.cn;http://orcid.org/0000-0002-6581-9987
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来翀 等. 转移性肾细胞癌靶向治疗的分子生物学基础[J]. 浙江大学学报（医学版）, 2016, 45(1): 91-97.
LAI Chong, TENG Xiaodong. Molecular biological foundation of targeted therapy for metastatic renal cell carcinoma. Journal of ZheJiang University(Medical Science), 2016, 45(1): 91-97.

链接本文:

http://www.zjujournals.com/xueshu/med/CN/10.3785/j.issn.1008-9292.2016.01.15      或      http://www.zjujournals.com/xueshu/med/CN/Y2016/V45/I1/91

[1] GIRGIS H, MASUI O, WHITE N M, et al. Lactate dehydrogenase A is a potential prognostic marker in clear cell renal cell carcinoma[J]. Mol Cancer, 2014, 13:101.
[2] SIEGEL R L, FEDEWA S A, MILLER K D, et al. Cancer statistics for Hispanics/Latinos, 2015[J]. CA Cancer J Clin, 2015, 65(6):457-480.
[3] FERLAY J, SHIN H R, BRAY F, et al. Estimates of worldwide burden of cancer in 2008:GLOBOCAN 2008[J]. Int J Cancer, 2010, 127(12):2893-2917.
[4] 吴阶平,那彦群,叶章群,等. 2014版中国泌尿外科疾病诊断治疗指南[M].北京:人民卫生出版社,2013:3-10. WU Jieping, NA Yanqun, YE Zhangqun, et al. Chinese association of urology guidelines the 2014 edition[M]. Beijing:People's Medical Publishing House, 2013:3-10.(in Chinese)
[5] MOTZER R J, BANDER N H, NANUS D M. Renal-cell carcinoma[J]. N Eng J Med, 1996, 335(12):865-875.
[6] TENG J, GAO Y, CHEN M, et al. Prognostic value of clinical and pathological factors for surgically treated localized clear cell renal cell carcinoma[J]. Chin Med J (Engl), 2014, 127(9):1640-1644.
[7] YANG F, ZHOU X, DU S, et al. LIM and SH3 domain protein 1(LASP-1) overexpression was associated with aggressive phenotype and poor prognosis in clear cell renal cell cancer[J]. PLoS One, 2014, 9(6):e100557.
[8] BABAIAN K N, MERRILL M M, MATIN S, et al. Partial nephrectomy in the setting of metastatic renal cell carcinoma[J]. J Urol, 2014, 192(1):36-42.
[9] EBLE J N, SAUTER G, EPSTEIN J I, et al. Pathology and genetics of tumors of the urinary system and male genital organs[M]. Lyon:World Health Organization International Agencg of Reserch on Cancer, 2004:10-40.
[10] 赵明, 滕晓东,孙柯,等. 新近认识的肾细胞癌[J]. 中华病理学杂志, 2013,42(7):478-482. ZHAO Ming, TENG Xiaodong, SUN Ke, et al. Recently identified renal cell carcinoma[J]. Chinese Journal of Pathology, 2013, 42(7):478-482. (in Chinese)
[11] CAIRNS P. Renal cell carcinoma[J]. Cancer Biomark, 2010, 9(1-6):461-473.
[12] SU D, SINGER E A, SRINIVAS A N R. Molecular pathways in renal cell carcinoma:recent advances in genetics and molecular biology[J]. Curr Opin Oncol, 2015, 27(3):217-223.
[13] DALGLIESH G L, FURGE K, GREENMAN C, et al. Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes[J]. Nature, 2010, 463(7279):360-363.
[14] DULAIMI E, IBANEZ DE CACERES I, UZZO R G, et al. Promoter hypermethylation profile of kidney cancer[J]. Clin Cancer Res, 2004,10(12 Pt 1):3972-3979.
[15] VARELA I, TARPEY P, RAINE K, et al. Exome sequencing identifies frequent mutation of the SWI/SNF complex gene PBRM1 in renal carcinoma[J]. Nature, 2011, 469(7331):539-542.
[16] Cancer Genome Atlas Research Network. Comprehensive molecular characterization of clear cell renal cell carcinoma[J]. Nature, 2013, 499(7456):43-49.
[17] KAPUR P, PEÑA-LIOPIS S, CHRISTIE A, et al. Effects on survival of BAP1 and PBRM1 mutations in sporadic clear-cell renal-cell carcinoma:a retrospective analysis with independent validation[J]. Lancet Oncol, 2013, 14(2):159-167.
[18] EDMUNDS J W, MAHADEVAN L C, CLAYTON A L. Dynamic histone H3 methylation during gene induction:HYPB/Setd2 mediates all H3K36 trimethylation[J]. EMBO J, 2008, 27(2):406-420.
[19] LI F, MAO G, TONG D, et al. The histone mark H3K36me3 regulates human DNA mismatch repair through its interaction with MutSα[J]. Cell, 2013, 153(3):590-600.
[20] PEÑA-LIOPIS S, VEGA-RUBÍN-DE-CELIS S, LIAO A, et al. BAP1 loss defines a new class of renal cell carcinoma[J]. Nat Genet, 2012, 44(7):751-759.
[21] SATO Y, YOSHIZATO T, SHIRAISHI Y, et al. Integrated molecular analysis of clear-cell renal cell carcinoma[J]. Nat Genet, 2013, 45(8):860-867.
[22] GORDAN J D, LAL P, DONDETI V R, et al. HIF-alpha effects on c-Myc distinguish two subtypes of sporadic VHL-deficient clear cell renal carcinoma[J]. Cancer Cell, 2008, 14(6):435-446.
[23] MONZON J G, HENG D Y. Management of metastatic kidney cancer in the era of personalized medicine[J]. Crit Rev Clin Lab Sci, 2014, 51(2):85-97.
[24] BRAHMER J R, DRAKE C G, WOLLNER I, et al. Phase I study of single-agent anti-programmed death-1(MDX-1106) in refractory solid tumors:safety, clinical activity, pharmacodynamics, and immunologic correlates[J]. J Clin Oncol, 2010, 28(19):3167-3175.
[25] ZHA Y Y, BLANK C, GAJEWSKI T F. Negative regulation of T-cell function by PD-1[J]. Crit Rev Immunol, 2004, 24(4):229-237.
[26] LAW C L, GORDON K A, TOKI B E, et al. Lymphocyte activation antigen CD70 expressed by renal cell carcinoma is a potential therapeutic target for anti-CD70 antibody-drug conjugates[J]. Cancer Res, 2006, 66(4):2328-2337.
[27] BUSSOLATI B, BROSSA A, CAMUSSI G. Resident stem cells and renal carcinoma[J]. Int J Nephrol, 2011, 2011:286985.
[28] BUSSOLATI B, BRUNO S, GRANGE C, et al. Identification of a tumor-initiating stem cell population in human renal carcinomas[J]. FASEB J, 2008, 22(10):3696-3705.
[29] KANESVARAN R, TAN M H. Targeted therapy for renal cell carcinoma:the next lap[J]. J Carcinog, 2014, 13:3.
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