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Predictive biomarkers in renal cell cancer: insights in drug resistance mechanisms.
Drug Resistance Updates ( IF 24.3 ) Pub Date : 2014-12-03 , DOI: 10.1016/j.drup.2014.10.003
Johannes C van der Mijn 1 , James W Mier 2 , Henk J Broxterman 3 , Henk M Verheul 3
Affiliation  

INTRODUCTION VEGF-targeted therapy is currently the first line treatment for patients with metastatic clear cell renal cell carcinoma (ccRCC), but most patients either display primary (intrinsic) resistance or acquire drug resistance. In recent years multiple mechanisms of resistance to VEGF-targeted therapy emerged from preclinical research, but it is currently unknown to what extent these drug resistance modalities play a role in the clinic. Here we reviewed the current literature on biomarkers that predict treatment outcome in patients with ccRCC to gain insight in clinical drug resistance mechanisms. METHODS A search syntax was compiled by combining different synonyms of "biomarker" AND "renal" AND "cancer". MEDLINE was accessed through PubMed, where this syntax was entered and used to search titles and abstracts of publications. Articles were selected based on three criteria: (1) description of patients with clear cell RCC, (2) treatment with VEGF targeted therapy and (3) discussion of biomarkers that were studied for potential association with treatment response. RESULTS The literature search was performed on March 4th 2014 and yielded 1882 articles. After carefully reading the titles and abstracts based on the three previously mentioned criteria, 103 publications were evaluated. Backward citation screening was performed on all eligible studies and revealed another 24 articles. This search revealed that (1) High glucose uptake and low contrast enhancement on PET- and CT-imaging before start of treatment may correlate with poor response to therapy, (2) Low dose intensity due to treatment intolerance is related to shorter progression free survival. (3) Acquired resistance appears to be associated with rebound vascularization based on both longitudinal monitoring of contrast enhancement by CT and blood vessel counts in tumor tissue, and (4) Based on plasma cytokine and single nucleotide polymorphism (SNP) studies, interleukin-8, VEGFR-3, FGFR2 and HGF/MET emerged as potential clinical markers for chemoresistance. CONCLUSION Low dose intensity, specific tumor-imaging techniques and potential biological biomarkers may be predictive for response to VEGF-targeted therapy in ccRCC. Some of these plausible biomarkers may also provide more insight into the underlying mechanisms of resistance such as altered glucose metabolism and rapid rebound vascularization.

中文翻译:

肾细胞癌中的预测性生物标志物:耐药机制的见解。

引言VEGF靶向治疗目前是转移性透明细胞肾细胞癌(ccRCC)患者的一线治疗,但是大多数患者表现出原发性(内在)耐药性或获得耐药性。近年来,从临床前研究中发现了多种针对VEGF靶向治疗的耐药性机制,但目前尚不清楚这些耐药性在临床上的作用程度。在这里,我们回顾了有关生物标志物的最新文献,这些文献预测了ccRCC患者的治疗结果,以了解临床耐药机制。方法通过组合“生物标志物”和“肾”和“癌症”的不同同义词来编译搜索语法。MEDLINE是通过PubMed访问的,输入此语法并用于搜索出版物标题和摘要的位置。根据以下三个标准选择文章:(1)对透明细胞RCC患者的描述,(2)VEGF靶向治疗,以及(3)讨论了与治疗反应可能相关的生物标志物。结果文献检索于2014年3月4日进行,产生了1882篇文章。在根据前面提到的三个标准仔细阅读标题和摘要之后,对103个出版物进行了评估。对所有符合条件的研究均进行了向后引文筛选,并发现了另外24篇文章。这项研究发现:(1)治疗开始前PET和CT成像的高葡萄糖摄取和低对比度增强可能与对治疗的不良反应相关,(2)由于治疗不耐受导致的低剂量强度与较短的无进展生存期有关。(3)根据纵向CT对比增强监测和肿瘤组织血管计数,获得性耐药似乎与反弹血管形成有关,(4)基于血浆细胞因子和单核苷酸多态性(SNP)研究,白细胞介素8 ,VEGFR-3,FGFR2和HGF / MET成为化学抗药性的潜在临床标志。结论低剂量强度,特异的肿瘤成像技术和潜在的生物标志物可预测ccRCC对VEGF靶向治疗的反应。这些似乎合理的生物标记物中的一些也可能提供对耐药性潜在机制的更多见解,例如改变的葡萄糖代谢和快速反弹的血管生成。
更新日期:2019-11-01
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