Division of Hematology-Oncology, Department of Medicine, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA.
David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA.
Clin Genitourin Cancer. 2018 Apr;16(2):e269-e276. doi: 10.1016/j.clgc.2017.10.011. Epub 2017 Nov 3.
The phosphoinositide 3 kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway is a well studied signaling pathway that regulates diverse cellular functions including proliferation, metabolism, and transcription. Aberrant activation of this pathway has been implicated in multiple cancers. Genomic studies have shown that activating mutations in oncogenes as well as inactivating mutations in tumor suppressor genes are present across a variety of malignancies, including urothelial carcinoma. In bladder cancer, up to 40% of tumors exhibit constitutive activation of the PI3K/AKT/mTOR pathway. Current treatments for non-muscle-invasive disease confer a 5-year cancer-specific survival rate as high as 90%. However, patients with muscle-invasive, recurrent, or metastatic disease have a poor prognosis. Although the introduction of immune checkpoint inhibitors is certainly changing the therapeutic landscape and is a great addition to the platinum-based therapy that was the standard of care for the past 3 decades, it is anticipated that a great number of patients would fail to respond or their disease would progress with either chemotherapy or immunotherapy. Therefore, the use of agents that target members of the PI3K/AKT/mTOR pathway represent an attractive, alternative therapeutic strategy for patients with advanced urothelial carcinoma. In this review we describe the pathway, with a focus on the rationale for targeting the PI3K/AKT/mTOR pathway in patients with advanced urothelial carcinoma and considers the challenges that we face from the current clinical trials. Novel agents such as PI3K inhibitors and microRNA inhibitors that target this pathway might lead to durable responses especially when used in combination with chemotherapy or immune checkpoint inhibitors, however, toxicity remains an obstacle. Finally, in this review we discuss the importance of developing biomarkers to help select appropriate patients and identify optimal treatment options.
磷酸肌醇 3 激酶（PI3K）/蛋白激酶 B（AKT）/哺乳动物雷帕霉素靶蛋白（mTOR）通路是一条研究得很好的信号通路，调节多种细胞功能，包括增殖、代谢和转录。该通路的异常激活与多种癌症有关。基因组研究表明，致癌基因的激活突变以及肿瘤抑制基因的失活突变存在于多种恶性肿瘤中，包括尿路上皮癌。在膀胱癌中，高达 40%的肿瘤表现出 PI3K/AKT/mTOR 通路的组成性激活。目前针对非肌肉浸润性疾病的治疗方法可使癌症特异性 5 年生存率高达 90%。然而，患有肌肉浸润性、复发性或转移性疾病的患者预后较差。尽管免疫检查点抑制剂的引入肯定正在改变治疗格局，并且是过去 30 年标准护理的基于铂类治疗的重要补充，但预计许多患者将无法响应或他们的疾病将随着化疗或免疫疗法而进展。因此，针对 PI3K/AKT/mTOR 通路成员的药物代表了一种有吸引力的替代治疗策略，适用于晚期尿路上皮癌患者。在这篇综述中，我们描述了该通路，重点介绍了针对晚期尿路上皮癌患者靶向 PI3K/AKT/mTOR 通路的原理，并考虑了我们目前面临的临床试验的挑战。新型药物，如针对该通路的 PI3K 抑制剂和 microRNA 抑制剂，可能会导致持久的反应，特别是当与化疗或免疫检查点抑制剂联合使用时，然而，毒性仍然是一个障碍。最后，在这篇综述中，我们讨论了开发生物标志物的重要性，以帮助选择合适的患者并确定最佳治疗方案。
