Targeted Therapy for Locally Advanced or Metastatic Urothelial Cancer (mUC): Therapeutic Potential of Sacituzumab Govitecan

Abstract

Urothelial carcinoma is the second most frequent genitourinary malignancy. Despite the poor prognosis, new treatment options have emerged and have expanded the therapeutic landscape for the disease. Although major improvements have been achieved, many patients experience rapid disease progression and low responses in subsequent lines of therapy. Sacituzumab govitecan is an ADC that targets Trop-2, which is highly expressed in urothelial cancers. Promising results in early clinical trials have led to further drug development which confirmed encouraging efficacy. Sacituzumab govitecan has been given accelerated approval in 2021 for patients with locally advanced and metastatic urothelial cancer who previously received a platinum containing chemotherapy and either a programmed death receptor-1 or programmed death ligand inhibitor. The results are promising, with encouraging efficacy and safety, however responses are not universal. There is a growing comprehension of mechanisms of resistance and predictive biomarkers that are crucial to improving outcomes. In this review, we summarize the current knowledge on antibody-drug conjugates and the clinical findings that led to the approval of Sacituzumab govitecan and discuss the therapeutic potential of new combinations, mechanisms of resistance and predictive biomarkers.

Targeted therapies in bladder cancer: signaling pathways, applications, and challenges

“…Most chemotherapy is difficult to apply to ADCs due to systemic cytotoxicity and dose limitations. To overcome these limitations, the IC50 of ideal payload should be in the picomolar or nanomolar concentrations range 125 . Therefore, highly toxic molecules are always selected as cytotoxic agents which comprise the ADCs payloads 119 .…”

“…To overcome these limitations, the IC50 of ideal payload should be in the picomolar or nanomolar concentrations range. 125 Therefore, highly toxic molecules are always selected as cytotoxic agents which comprise the ADCs payloads. 119 Cytotoxic agents are classified into those damaging DNA (calicheamicin, pyrrolobenzodiazepine (PBD), duocarmycin, and topoisomerase inhibitors), and those altering tubulin formation (tubulysin, auristatin derivatives, and maytansinoids).…”

“…After entering endosomes or lysosomes, the ADCs payloads are detached from the antibody carriers due to acidic, proteolytic, or redox conditions. They then scatter into the cytosol and attack target substrates, eventually leading to cancer cell death via targeting microtubules or DNA 125,127 . In addition, if the payload is permeable or transmembrane, its release may also enhanced the cytotoxic effects of ADCs by generating bystander effects to directly or indirectly altering the tumor microenvironment 128 …”

Interaction of Camptothecin Anticancer Drugs with Ribosomal Proteins L15 and L11: A Molecular Docking Study

“…The last drug is the antibody–drug conjugate (ADC) sacituzumab govitecan (SG), which combines an anti-TROP-2 (trophoblast cell-surface antigen 2) antibody coupled to SN-38. This ADC is used to treat patients with metastatic triple-negative breast cancer and those with locally advanced and metastatic urothelial cancer [ 8 , 9 , 10 ]. These five drugs target topoisomerase I, a four-decade-old target that remains an attractive protein for drug design.…”