Precision Medicine in the Treatment of Locally Advanced or Metastatic Urothelial Cancer: New Molecular Targets and Pharmacological Therapies

SIMPLE SUMMARY: Therapeutic breakthroughs in urothelial carcinoma have been occurring rapidly over the past 10 years. However, the resistance and prognosis of this disease is always quite a difficult health challenge. Trying to understand the new therapeutic perspectives is a priority to try to bring in new drug models that can counteract the advancing prognosis and inauspicious diagnosis. ABSTRACT: 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.