Potential Role for Targeted Therapy in Muscle-Invasive Bladder Cancer

The Cancer Genome Atlas project has identified and confirmed several important molecular alterations that form the basis for tumorigenesis and disease progression in muscle-invasive bladder cancer. Profiling studies also have reported on validated biomarker panels that predict prognosis and may be used to identify patients who require more aggressive therapy. This article describes the major molecular alterations in muscle-invasive urothelial carcinoma, and how several of these are being investigated as targets for novel therapeutics. It also highlights studies that identify biomarkers for platinum sensitivity, and efforts to integrate targeted therapeutics and companion theranostics for personalized treatment of muscle-invasive bladder cancer.

Key points

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Efforts of The Cancer Genome Atlas (TCGA) project and other studies have greatly advanced our understanding of genomic alterations associated with muscle-invasive bladder cancer.
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Alterations in tyrosine kinase receptors, intracellular signaling pathways, cell cycle regulators, molecular chaperones, and mediators of angiogenesis and immune response can influence bladder cancer progression and act as therapeutic targets.
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Recent whole-genome profiling studies have identified biomarker panels that can predict prognosis and may be used to identify patients who need more aggressive therapy.
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Combining surgical advances, novel targeted therapeutics, and companion theranostics represents the new paradigm for personalized treatment of muscle-invasive bladder cancer.

Genomic landscape of bladder cancer

Urothelial carcinoma of the bladder (UCB) has now been recognized as evolving and progressing through at least 2 distinct molecular pathways. Nearly 70% of low-grade noninvasive papillary tumors, which generally tend to recur locally but rarely invade and metastasize, show constitutive activation of the receptor tyrosine kinase (RTK)-Ras pathway, with activating mutations in HRAS and fibroblast growth factor receptor 3 ( FGFR3 ) genes. In contrast, carcinoma in situ (CIS) and invasive tumors show frequent alterations in the TP53 and retinoblastoma ( RB ) genes and pathways.

Although previous efforts using targeted molecular analyses have elucidated several pathways that are important for bladder tumorigenesis and cancer progression, the advent of high-throughput profiling strategies has enabled comprehensive characterization of genomic alterations for the disease. Several studies have used this approach to identify genomic loci associated with the risk of developing UCB and characterizing clonal development across various disease stages.

Leveraging advances in whole-genome expression profiling, next-generation sequencing, microarray analysis, and methylation arrays, The Cancer Genome Atlas (TCGA) project has comprehensively profiled 131 high-grade muscle-invasive UCBs. This effort has cataloged genes that are mutated in a significant proportion of bladder cancers, several of which were not previously reported ( Table 1 ). The analysis suggested that the burden of genetic alterations in UCB is similar to lung adenocarcinoma and squamous cell carcinoma and melanoma, but more than in other adult malignancies.

Table 1

Summary of significantly mutated genes identified by The Cancer Genome Atlas project in muscle-invasive bladder cancer

Pathway/Function and Associated Gene(s)	Number of Nonsilent Mutations	Significant Association ^a
Signal transduction
PIK3CA ^b^,^c	26
FGFR3 ^b^,^c	21	Tumor subtype ^d
ERBB3 ^b^,^c	14	Tumor subtype ^d
ERBB2 ^c	11
TSC1 ^b	11	Tumor subtype ^d
RHOB ^b	7
HRAS ^b^,^c	6
RHOA ^b	5
CTNNB1 ^c	3
Cell cycle regulation
TP53 ^b^,^c	75	Tumor subtype ^d
RB1 ^b^,^c	19	Survival
CDKN1A ^b	18
STAG2 ^b	14
CDKN2A ^b^,^c	8	Disease stage
HORMAD1 ^b	8
BTG2 ^b	6
CCND3 ^b	5
Transcriptional regulation
ELF3 ^b	15	Disease stage
NFE2L2 ^b	12
RXRA ^b	12
KLF5 ^b	11
TXNIP ^b	10
FOXA1 ^b	7
FOXQ1 ^b	7
PAIP1 ^b	7
ZFP36L1 ^b	6
ZFR2 ^b	6
DNA damage response
ATM ^c	19
ERCC2 ^b	16
Histone modification/Chromatin remodeling
ARID1A ^b	39
MLL2 ^b	39	Survival
KDM6A ^b	32
EP300 ^b	25
Ubiquitination
FBXW7 ^b^,^c	16	Survival
Cell surface proteoglycan
GPC5 ^b	8