Targets for Therapy of Bladder Cancer

Abstract

In 2018 bladder cancer (urothelial carcinoma) was ranked twelfth concerning worldwide diagnosis of malignancies. At the time point of diagnosis of bladder cancer, approximately 75% of patients present with a nonmuscle-invasive disease (NMIBC), while the remaining 25% show invasion of tumor cells in the muscle layer of the bladder wall (MIBC). Among NMIBC tumors, flat, high-grade carcinoma in situ (CIS) is a therapeutic challenge. CIS shows a tendency to invade the muscle tissue of the bladder wall and thus become a MIBC. Standard therapy of NMIBC (including CIS) is done via intravesical instillation of BCG (bacillus Calmette Guerin) inducing a local immune reaction that finally promotes elimination of bladder cancer cells. However, BCG treatment of NMIBC proves to be ineffective in approximately 40% of patients. Therefore, new therapeutic approaches for the treatment of bladder cancer are urgently needed. Among promising new treatment options that are currently being investigated are the use of immune checkpoint inhibitors, and targeted approaches attacking (among others) long noncoding RNAs, micro RNAs, cancer stem cells, PARP1, and receptor signaling pathways. Moreover, the use of antibody-drug-conjugates (ADCs) is investigated also in bladder cancer therapy. Another approach that has been successfully established in preclinical studies uses the cytotoxic power of the alpha-emitter Bi-213 coupled to an antibody targeting EGFR. Overexpression of EGFR has been demonstrated in the majority of patients suffering from CIS. Feasibility, safety, toxicity and therapeutic efficacy of intravesical instillation of Bi-213-anti-EGFR have been evaluated in a pilot study. Since the results of the pilot study proved to be promising, a further optimization of alpha-emitter immunotherapy in bladder cancer seems mandatory.