Vitiello Antonio, Ferrara Francesco, Lasala Ruggero, Zovi Andrea
Ministry of Health, Viale Giorgio Ribotta 5, 00144 Rome, Italy.
Pharmaceutical Department, Local Health Unit Napoli 3 Sud, Dell'amicizia Street 22, 80035 Nola, Italy.
Cancers (Basel). 2022 Oct 21;14(20):5167. doi: 10.3390/cancers14205167.
Many variants of urothelial cancer present diagnostic challenges and carry clinical implications that influence prognosis and treatment decisions. The critical issues of treatment-resistant clones are a crucial barrier to care in individuals affected by urothelial carcinoma. Laying the foundations for the resistance evolution, a wide mutational heterogeneity characterizes urothelial carcinoma, noticeable also in patients affected by a early stage disease. In recent years the growing knowledge of the pathogenesis and molecular paths underlying the onset and progression of urothelial cancer are leading to the development of new therapies based on immune checkpoints. Chemotherapy and immunotherapy both operate selectively by shaping the developmental trajectory of urothelial carcinoma in the course of the illness. To date, a promising new therapeutic treatment is represented by antibody-drug conjugates, therapeutic tools that exploit the targeted ability of an antibody to administer cytotoxic drugs directly to the tumor. Indeed, nowadays in the clinical setting there are several treatments available for the treatment of locally advanced or metastatic urothelial cancer, from classic chemotherapeutics such as Gemcitabine, Cisplatin and Carboplatin, Paclitaxel and Docetaxel, to Programmed cell death protein 1 (PD-1) or Programmed death-ligand 1 (PD-L1) inhibitors such as Atezolizumab, Avelumab, Nivolumab, Pembrolizumab, up to anti-nectin 4 Enfortumab Vedotin and Sacituzumab govitecan, which binds Tumor-associated calcium signal transducer 2 (Trop-2) and activates as a topoisomerase inhibitor. The aim of this work is to describe the molecular mechanisms underlying the onset of the urothelial cancer and provide an overview of the immunotherapies that can be used in the clinical setting to counteract it, deepening the efficacy and safety results of the pivotal studies and the place in therapy of these treatments.
许多尿路上皮癌变体带来了诊断挑战，并具有影响预后和治疗决策的临床意义。治疗耐药克隆的关键问题是尿路上皮癌患者护理的关键障碍。尿路上皮癌具有广泛的突变异质性，这为耐药性演变奠定了基础，在早期疾病患者中也很明显。近年来，对尿路上皮癌发病机制和分子途径的认识不断增加，促使基于免疫检查点的新疗法不断发展。化疗和免疫疗法都通过在疾病过程中塑造尿路上皮癌的发展轨迹来发挥选择性作用。迄今为止，一种有前景的新治疗方法是抗体药物偶联物，这种治疗工具利用抗体的靶向能力将细胞毒性药物直接输送到肿瘤。事实上，如今在临床环境中，有几种治疗方法可用于治疗局部晚期或转移性尿路上皮癌，从经典化疗药物如吉西他滨、顺铂和卡铂、紫杉醇和多西他赛，到程序性细胞死亡蛋白1（PD-1）或程序性死亡配体1（PD-L1）抑制剂如阿替利珠单抗、阿维鲁单抗、纳武利尤单抗、帕博利珠单抗，再到抗Nectin 4抗体偶联药物安罗替尼和戈沙妥珠单抗，后者与肿瘤相关钙信号转导蛋白2（Trop-2）结合并作为拓扑异构酶抑制剂发挥作用。这项工作的目的是描述尿路上皮癌发病的分子机制，并概述可在临床环境中用于对抗它的免疫疗法，深入探讨关键研究的疗效和安全性结果以及这些治疗方法在治疗中的地位。
