TRAIL-mediated signaling in bladder cancer: realization of clinical efficacy of TRAIL-based therapeutics in medical oncology

Bladder cancer is a therapeutically challenging disease and wealth of knowledge has enabled researchers to develop a clear understanding of mechanisms which underlie carcinogenesis and metastasis. Excitingly, research over decades has unveiled wide-ranging mechanisms which serve as central engine in progression of bladder cancer. Loss of apoptosis, drug resistance, and pro-survival signaling are some of the highly studied cellular mechanisms. Therefore, restoration of apoptosis in resistant cancers is a valuable and attractive strategy. Discovery of TRAIL-mediated signaling cascade is an intriguing facet of molecular oncology. In this review, we have provided an overview of the translational and foundational advancements in dissecting the genomic and proteomic cartography of TRAIL signaling exclusively in the context of bladder cancer. We have also summarized how different natural products sensitized drug-resistant bladder cancer cells to TRAIL-mediated apoptosis. Interestingly, different death receptors that activate agonistic antibodies have been tested in various phases of clinical trials against different cancers. Certain clues of scientific evidence have provided encouraging results about efficacy of these agonistic antibodies (lexatumumab and mapatumumab) against bladder cancer cell lines. Therefore, multipronged approaches consisting of natural products, chemotherapeutics, and agonistic antibodies will realistically and mechanistically provide proof-of-concept for the translational potential of these combinatorial strategies in well-designed clinical trials.

Automated summary

Bladder cancer is a challenging disease, and researchers have made significant progress in understanding the mechanisms underlying its development and progression. Restoring apoptosis in drug-resistant cancers, particularly through TRAIL-mediated signaling, shows promise as a valuable treatment strategy. Various natural products and agonistic antibodies have been tested in clinical trials, demonstrating encouraging results in sensitizing drug-resistant bladder cancer cells to apoptosis. Multipronged approaches combining natural products, chemotherapeutics, and agonistic antibodies show potential in well-designed clinical trials.