Molecularly Targeted Therapy towards Genetic Alterations in Advanced Bladder Cancer

Abstract

Despite the introduction of immune checkpoint inhibitors and antibody–drug conjugates to the management of advanced urothelial carcinoma, the disease is generally incurable. The increasing incorporation of next-generation sequencing of tumor tissue into the characterization of bladder cancer has led to a better understanding of the somatic genetic aberrations potentially involved in its pathogenesis. Genetic alterations have been observed in kinases, such as FGFRs, ErbBs, PI3K/Akt/mTOR, and Ras-MAPK, and genetic alterations in critical cellular processes, such as chromatin remodeling, cell cycle regulation, and DNA damage repair. However, activating mutations or fusions of FGFR2 and FGFR3 remains the only validated therapeutically actionable alteration, with erdafitinib as the only targeted agent currently approved for this group. Bladder cancer is characterized by genomic heterogeneity and a high tumor mutation burden. This review highlights the potential relevance of aberrations and discusses the current status of targeted therapies directed at them.

Clinical implications and practical considerations for poly-ADP-ribose polymerase inhibitors as a new horizon for the management of urothelial carcinoma of the bladder

“…Activating mutations or fusions of fibroblast growth factor receptor (FGFR) 2 and FGFR3 have been validated as therapeutically actionable alterations, with erdafitinib currently approved for locally advanced or metastatic urothelial carcinoma of the bladder (a/m UCB) [ 5 ]. Several other potentially targetable genomic alterations have been implicated in a/m UCB, including alterations related to ErbB receptors, PI3K/Akt/mTOR pathway, Ras/MAPK pathway, chromatin remodeling, cell cycle regulation, and HRR [ 5 ].…”

“…Activating mutations or fusions of fibroblast growth factor receptor (FGFR) 2 and FGFR3 have been validated as therapeutically actionable alterations, with erdafitinib currently approved for locally advanced or metastatic urothelial carcinoma of the bladder (a/m UCB) [ 5 ]. Several other potentially targetable genomic alterations have been implicated in a/m UCB, including alterations related to ErbB receptors, PI3K/Akt/mTOR pathway, Ras/MAPK pathway, chromatin remodeling, cell cycle regulation, and HRR [ 5 ]. Recently, a/m UCB was shown to have a high prevalence of pathogenic germline and somatic mutations in several HRR genes (23%–34%), such as CHK1/2 , RAD51 , BRCA1/2 , ATM , ATR , MDC1 , RAD52 , and FANCF [ 1 6 7 8 9 ], suggesting the possibility of PARPi and synthetic lethality strategies exploiting HRD in a/m UCB.…”

Advances in diagnosis and treatment of bladder cancer

“…While platinum based chemotherapy remains an important component of treatment for patients with metastatic disease, emerging novel treatments, including approved antibody-drug conjugates and targeted treatments, have represented a paradigm shift in managing metastatic bladder cancer 9152526272829303132. Immune checkpoint inhibitors remain helpful in these patients, particularly those with high tumor mutation load and expression of programmed death ligand 1 (PDL1) (tumor mutational burden (TMB) high /PDL1 + ) 3334.…”

Urine-derived bladder cancer organoids (urinoids) as tool for cancer longitudinal response monitoring and therapy adaptation

“…However, it remains challenging to apply such information in clinical practice to guide treatment decision-making 59,17 . In addition, drug treatment itself may induce changes in tumor characteristics, such as genetic instability, and cause enrichment of speci c molecular subclones, which may result in altered drug-sensitivity and acquired drug-resistance [17][18][19][20] . Platforms that allow drug-response monitoring longitudinally may therefore have great value in developing personalized and adaptive treatment strategies.…”