Dataset Information

Novel molecular targets for urothelial carcinoma.

ABSTRACT:

Introduction

Urothelial cancer (UC) remains a significant public health problem, with no new second-line agents FDA-approved in the US. Next-generation sequencing technologies are starting to generate a molecular landscape of UC thus revealing novel molecular targets.

Areas covered

In this review, the authors provide a detailed review of novel molecular targets in UC based on published genomic analyses of urothelial tumors. We provide an overview of each molecular target with a brief discussion of therapeutic strategies and clinical trials targeting each pathway.

Expert opinion

UC continues to be a lethal disease with no FDA-approved effective second-line therapies. Platinum resistance continues to be a daunting clinical problem. Next-generation sequencing methods have led to the elucidation of numerous molecular targets in UC, including PI3K, to the elucidation of numerous molecular targets in UC, including PI3K, ERBB2 and FGFR3, among many others. These molecular perturbations can be exploited therapeutically with targeted therapies in patient populations enriched for these molecular alterations, thus paving the way for precision medicine in UC management.

SUBMITTER: Faltas BM

PROVIDER: S-EPMC4406627 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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Publications

Novel molecular targets for urothelial carcinoma.

Faltas Bishoy M BM Karir Beerinder S BS Tagawa Scott T ST Rosenberg Jonathan E JE

Expert opinion on therapeutic targets 20150130 4

<h4>Introduction</h4>Urothelial cancer (UC) remains a significant public health problem, with no new second-line agents FDA-approved in the US. Next-generation sequencing technologies are starting to generate a molecular landscape of UC thus revealing novel molecular targets.<h4>Areas covered</h4>In this review, the authors provide a detailed review of novel molecular targets in UC based on published genomic analyses of urothelial tumors. We provide an overview of each molecular target with a br ...[more]

PMID: 25633079

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Project description:Even though urothelial cancer (UC) is the fourth common tumor type among males, progress in treatment development has been deficient. Pathological assessment provides the urologists with only a broad classification, complicated by frequent disagreement among pathologist and the co-existence of different grading systems. Consequently, there is a great need for an objective, reproducible and biologically relevant classification system to make treatment more efficient. In the present investigation we present a molecular taxonomy for UC stratification based on integrated genomics. We used gene expression profiles from 308 UC to define seven molecular subtypes using step-by-step partitions and a bootstrap approach. Results were validated in three independent and publically available data sets. The subtypes differ significantly with respect to expression of cell cycle genes, of receptor tyrosine kinases particularity FGFR3, ERBB2 (HER2), and EGFR, of an FGFR3 associated gene expression signature, of cytokaratins, and of cell adhesion genes. The subtypes also differ significantly with respect to FGFR3, PIK3CA, and TP53 mutations. The expression of key proteins was validated by IHC on TMA. A further inspection indicated that the subtypes could be reduced to four major types of UC; Urobasal/D-driven, Genomically unstable/E-driven, Evolved urobasal, and Basal/SCC like, with characteristic and highly divergent molecular phenotypes. We show that the molecular subtypes cut across pathological classification and that tumors classified as one subtype maintain their characteristic molecular phenotype irrespective of pathological stage and grade. Available data from the Drugbank database and the Cochrane central registry of controlled trials indicate that susceptibility to specific drugs is more likely to be associated with the molecular stratification than with pathological classification. The presented molecular taxonomy stratifies UC into subtypes with distinct molecular phenotypes and biological properties. We anticipate that the molecular taxonomy will be a useful tool in future clinical investigations. Total RNA from fresh-frozen resection samples of 308 urothelial carcinomas was hybridized to the Illumina HumanHT-12 V3.0 expression beadchip arrays (Illumina Inc) at the SCIBLU Genomics Centre at Lund University Sweden (http://www.lth.se/sciblu). Supplementary files: GSE32894_non-normalized_308UCsamples.txt file = Raw intensity values for 308 UC (urothelial tumor) samples subjected only to background correction. GSE32894_reps_normals_preprocess*.txt files = Descriptive details and non-normalized data for technical replicates and normal samples that were used only in the preprocessing of the data. This dataset partly overlaps with Series GSE32549. Names of the overlapping sample names are the same, but the title of each sample is unique to the hybridization.

Dataset Information

Novel molecular targets for urothelial carcinoma.

Introduction

Areas covered

Expert opinion

Publications

Novel molecular targets for urothelial carcinoma.

Similar Datasets

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