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治疗FGFR2驱动的胃癌的临床进展与挑战

Clinical Developments and Challenges in Treating FGFR2-Driven Gastric Cancer.

作者信息

Lau David K, Collin Jack P, Mariadason John M

机构信息

Olivia Newton-John Cancer Research Institute, Heidelberg, VIC 3084, Australia.

School of Cancer Medicine, La Trobe University, Heidelberg, VIC 3084, Australia.

出版信息

Biomedicines. 2024 May 17;12(5):1117. doi: 10.3390/biomedicines12051117.

Abstract

Recent advances in the treatment of gastric cancer (GC) with chemotherapy, immunotherapy, anti-angiogenic therapy and targeted therapies have yielded some improvement in survival outcomes; however, metastatic GC remains a lethal malignancy and amongst the leading causes of cancer-related mortality worldwide. Importantly, the ongoing molecular characterisation of GCs continues to uncover potentially actionable molecular targets. Among these, aberrant FGFR2-driven signalling, predominantly arising from amplification, occurs in approximately 3-11% of GCs. However, whilst several inhibitors of FGFR have been clinically tested to-date, there are currently no approved FGFR-directed therapies for GC. In this review, we summarise the significance of FGFR2 as an actionable therapeutic target in GC, examine the recent pre-clinical and clinical data supporting the use of small-molecule inhibitors, antibody-based therapies, as well as novel approaches such as proteolysis-targeting chimeras (PROTACs) for targeting FGFR2 in these tumours, and discuss the ongoing challenges and opportunities associated with their clinical development.

摘要

化疗、免疫疗法、抗血管生成疗法和靶向疗法在胃癌(GC)治疗方面的最新进展已使生存结果有所改善;然而,转移性胃癌仍然是一种致命的恶性肿瘤,也是全球癌症相关死亡的主要原因之一。重要的是,对胃癌不断进行的分子特征分析持续揭示出潜在的可操作分子靶点。其中,异常的FGFR2驱动信号主要由扩增引起,约3%-11%的胃癌中存在这种情况。然而,尽管目前已有几种FGFR抑制剂进行了临床试验,但目前尚无获批用于胃癌的FGFR靶向疗法。在本综述中,我们总结了FGFR2作为胃癌中一个可操作治疗靶点的重要性,研究了支持在这些肿瘤中使用小分子抑制剂、基于抗体的疗法以及诸如靶向蛋白水解嵌合体(PROTAC)等靶向FGFR2的新方法的最新临床前和临床数据,并讨论了其临床开发中持续存在的挑战和机遇。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dacf/11118914/0c6f0feda15a/biomedicines-12-01117-g001.jpg

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