Su Daniel, Singer Eric A, Srinivasan Ramaprasad
aUrologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland bSection of Urologic Oncology, Rutgers Cancer Institute of New Jersey and Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA.
Curr Opin Oncol. 2015 May;27(3):217-23. doi: 10.1097/CCO.0000000000000186.
Advanced renal cell carcinoma (RCC) remains a largely incurable disease with a grave prognosis despite the availability of a multiplicity of systemic therapies targeted against vascular endothelial growth factor, its receptors, and the mammalian target of rapamycin. Although immune 'checkpoint inhibitors' appear to have activity in clear cell RCC based on recent early phase trials, the true magnitude of the benefit conferred by these agents remains to be fully understood. Given the limitations of existing treatment paradigms, ongoing research into new targetable pathways is critical. This review will highlight some of the more promising avenues of investigation into the molecular biology of RCC.
The hypoxia-inducible factor and mammalian target of rapamycin pathways remain critical targets in clear cell RCC. In addition, genes involved in chromatin remodeling such as polybromo 1 (PBRM1), SET domain containing 2 (SETD2), and BRCA-1-associated protein-1 (BAP1) have been shown to influence tumor biology and predict survival. MET alterations and the Krebs cycle enzyme fumarate hydratase are associated with familial type 1 and type 2 papillary RCC (PRCC), respectively. Alterations in nuclear factor (erythroid-derived 2)-like 2, Kelch-like erythroid-derived cap-n-collar homology-associated protein 1, and cullin 3, components of an oxidative stress response pathway, have been recently recognized in some sporadic papillary tumors as well as in fumarate hydratase-deficient tumor and may serve as additional therapeutic targets. In addition, whole-genome sequencing and integrated genomic analysis strategies are beginning to uncover unique molecular signatures associated with distinct subtypes of RCC, laying the foundation for a molecular classification of RCC and more precise, mechanism-based therapeutic intervention.
The complex molecular changes underlying individual RCC variants are yet to be fully elucidated and remain the subject of ongoing investigation. The findings summarized here further exemplify the diversity of RCC and the need to tailor our therapeutic approaches to the unique genetic alterations specific to individual subtypes of RCC.
尽管有多种针对血管内皮生长因子、其受体以及雷帕霉素哺乳动物靶点的全身治疗方法，但晚期肾细胞癌（RCC）在很大程度上仍是一种无法治愈的疾病，预后严重。虽然基于近期的早期试验，免疫“检查点抑制剂”在透明细胞RCC中似乎具有活性，但这些药物所带来益处的真正程度仍有待充分了解。鉴于现有治疗模式的局限性，对新的可靶向通路进行持续研究至关重要。本综述将重点介绍一些在RCC分子生物学方面更有前景的研究途径。
缺氧诱导因子和雷帕霉素哺乳动物靶点通路在透明细胞RCC中仍然是关键靶点。此外，参与染色质重塑的基因，如多溴1（PBRM1）、含SET结构域2（SETD2）和BRCA1相关蛋白1（BAP1），已被证明会影响肿瘤生物学并预测生存。MET改变和三羧酸循环酶富马酸水合酶分别与家族性1型和2型乳头状RCC（PRCC）相关。核因子（红系衍生2）样2、Kelch样红系衍生帽-颈同源相关蛋白1和cullin 3（氧化应激反应通路的组成部分）的改变，最近在一些散发性乳头状肿瘤以及富马酸水合酶缺陷肿瘤中也被发现，可能成为额外的治疗靶点。此外，全基因组测序和综合基因组分析策略开始揭示与RCC不同亚型相关的独特分子特征，为RCC的分子分类以及更精确的、基于机制的治疗干预奠定了基础。
个体RCC变体背后复杂的分子变化尚未完全阐明，仍是正在进行的研究课题。此处总结的发现进一步例证了RCC的多样性以及根据RCC各亚型特有的独特基因改变来调整治疗方法的必要性。
