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Bladder Cancer Study Uncovers Potential Drug Targets and Molecular Similarities to Other Cancers

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Key Points

  • Researchers have identified new potential therapeutic targets for urothelial carcinoma of the bladder. They also found molecular similarities to some subtypes of breast, head and neck, and lung cancers.
  • Genes that regulate chromatin were found to be more frequently mutated in bladder cancer than in any other common cancer studied to date, suggesting the possibility of developing therapies to target alterations in chromatin remodeling.
  • Whole-genome and RNA sequencing also identified expression or integration of several viruses, including HPV16, suggesting that viral infection can contribute to the development of bladder cancer.

Investigators with The Cancer Genome Atlas Research Network have identified new potential therapeutic targets for urothelial carcinoma of the bladder, a common cancer that causes about 150,000 deaths worldwide each year. The researchers also found molecular similarities to some subtypes of breast, head and neck, and lung cancers, suggesting similar routes of development. The study is published in Nature.

In the study, researchers analyzed DNA, RNA, and protein data generated from a study of 131 high-grade muscle-invasive urothelial bladder carcinomas from patients who had not yet been treated with any type of therapy. They found recurrent mutations in 32 genes, including 9 genes not previously reported as significantly mutated in any cancer. Mutations in TP53 were discovered in nearly half of the tumor samples, and mutations and other aberrations in the RTK/RAS pathway were found in 44% of the tumor samples.

Potential Drug Targets

The study found that chromatin-regulating genes were more frequently mutated in bladder cancer than in any other common cancer studied to date, suggesting the possibility of developing therapies to target alterations in chromatin remodeling. For example, recently developed agents that bind acetyl-lysine binding motifs (bromodomains) might prove useful for the treatment of a subset of bladder tumors that have abnormalities in chromatin-modifying enzymes, according to the study. Overall, the researchers identified potential drug targets in 69% of the tumors evaluated.

The investigators found frequent mutations in the ERBB2 (or HER2) gene and identified recurring mutations as well as fusions involving FGFR3 and in the PI3 kinase/AKT/mTOR pathway, which help control cell division and growth and for which targeted drugs already exist.

“The real excitement about this project is that we now have a menu of treatment and research directions to pursue,” Seth P. Lerner, MD, Professor and Chair in Urologic Oncology at Baylor College of Medicine in Houston, and a lead author of the study, said in a statement. “The field is poised to use this information to make new advances toward therapies for a very difficult-to-treat form of bladder cancer.”

Other Risk Factors  

Whole-genome and RNA sequencing also identified expression or integration of several viruses, including HPV16, which are associated with gene activation, suggesting that viral infection can contribute to the development of bladder cancer.

More than 70% of the cases analyzed in this study occurred in former or current smokers, and tobacco is a known major risk factor for bladder cancer. However, the analysis did not identify major molecular differences between the tumors that developed in patients with or without a history of smoking.

According to the American Cancer Society, approximately 72,570 new cases of bladder cancer were diagnosed in the United States in 2013.

The study was supported by grants from the National Institutes of Health. The study authors reported no conflicts of interest.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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