The Current Progress and Future Options of Multiple Therapy and Potential Biomarkers for Muscle-Invasive Bladder Cancer

Abstract

Bladder cancer is a common disease in men and the elderly. Current treatment paradigms include radical resection of the bladder and lymph nodes or transurethral resection, both supported by chemotherapy and/or radiation. New modalities, such as illumination-based therapies are also being translationally pursued. However, while survival rates have increased due to combined therapies (particularly chemotherapy, radiation, immune checkpoint inhibitors, and surgery), a lack of diagnostic markers leads clinical professionals to rely on frequently invasive and expensive means of monitoring, such as magnetic resonance imaging or bladder cystoscopy. To improve real-time diagnostic capabilities, biomarkers that reflect both the metabolic and metastatic potential of tumor cells are needed. Furthermore, indicators of therapy resistance would allow for rapid changes in treatment to optimize survival outcomes. Fortunately, the presence of nanoscale extracellular vesicles in the blood, urine, and other peripheral fluids allow for proteomic, genomic, and transcriptomic analyses while limiting the invasiveness of frequent sampling. This review provides an overview of the pathogenesis and progression of bladder cancer, standard treatments and outcomes, some novel treatment studies, and the current status of biomarker and therapy development featuring exosome-based analysis and engineering.

Keywords: biomarker; diagnosis; exosome; muscle-invasive bladder cancer; therapeutics.

Figure 1

Bladder Cancer Pathogenesis. Early in situ carcinomas mature into Ta (Grade 1) and T1 (Grade 2) non-muscular invasive bladder cancers (NMIBC) malignancies that begin to penetrate the muscle wall of the bladder. Here, transurethral resection of the bladder (TURBT) and Bacillus Calmette–Guérin (BCG) therapy are often curative. However, a subpopulation is resistant to these therapies and the tumor penetrates the muscle wall and fatty tissue, becoming advanced-stage muscle-invasive bladder cancer (MIBC; Grades 3 and 4). With metastasis to surrounding organs, multimodal therapies featuring radical cystectomy (RC), neoadjuvant chemotherapy (NAC), and radiation (RAD) are used to increase survival by tumor growth and metastasis control. Created at BioRender.com.

Figure 2

The Proposed Exosome Cycle. Tumor exosomes can be frequently collected from urine and blood, purified in high volumes, analyzed via -omics technology, and used to evaluate both tumor metabolism and response to therapy. In addition to customizing therapy based on exosome analysis, exosomes engineered to deliver custom payloads to tumor cells to promote chemoradiation susceptibility and apoptosis can be used as a synergistic adjunct to surgery and chemoradiation therapies. Created at BioRender.com.