Bladder cancer study identifies therapeutic targets

San Francisco-A comprehensive molecular characterization of muscle-invasive urothelial bladder carcinoma suggests multiple opportunities for therapeutic intervention.

Researchers presented their findings from the large-scale Cancer Genome Atlas (TCGA) project at the Genitourinary Cancers Symposium in San Francisco, and the results were published in Nature (2014; 507:315-22).

Dr. RosenbergThere have been no new therapies for bladder cancer since the 1970s, explained lead author Jonathan Rosenberg, MD, section chief of the non-prostate program in the genitourinary oncology service at Memorial Sloan-Kettering Cancer Center, New York. He and his colleagues hope that the TCGA project will lead to identification of new therapies targeted to actionable mutations and provide clinical benefits in appropriately selected subsets of patients.

“There are two major take-home points from our work on the Cancer Genome Atlas in bladder cancer,” Dr. Rosenberg told Urology Times.

“The first is that the majority of patients with muscle-invasive urothelial bladder carcinoma have actionable mutations that can be targeted in selected populations with either FDA-approved drugs or investigational agents,” he emphasized.

The second is that epigenetic regulatory genes are frequently altered in this type of bladder cancer, suggesting that there may be a different paradigm for therapeutic intervention. Seventy-six percent of tumors had one inactivating epigenetic mutation and 41% had two. More clinical and laboratory research is needed with drugs that target these alterations, such as histone deacetylase inhibitors, DNA methyltransferase inhibitors, and bromodomain inhibitors.

“These drugs may prove useful in subsets of patients, depending on the mutation profile of epigenetic regulatory genes,” Dr. Rosenberg said.

As part of the TCGA project, the authors analyzed DNA from 131 muscle-invasive urothelial bladder cancer tumors and corresponding normal samples (predominantly blood). They determined that bladder cancer is one of the most highly mutated tumor types, with each tumor possessing an average of 302 exonic mutations, 204 segmental alterations in DNA copy number, and 22 large-scale genomic alterations. Thirty-two recurrent significantly mutated genes were identified that appear to be involved in bladder cancer pathogenesis.

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Some of these genetic abnormalities had not been previously reported in bladder cancer or in other cancers included in the TCGA, Dr. Rosenberg said.

Mutation spectrum, rate, and focal copy number alterations or expression subtypes do not correlate with exposure to cigarettes in this cohort; 72% of patients who provided these samples were current or former smokers.

Three clusters of abnormalities were identified based on an integrated analysis of both mutations and copy number: a genomic amplification cluster, a p16-deleted cluster, and a p53-mutated cluster.

“These clusters suggest that there may be different oncogenic mechanisms involved in the development of muscle-invasive bladder cancer, but we don’t know yet whether any of them are clinically relevant,” Dr. Rosenberg said.

In addition to mutations, 27 focal genomic amplifications and 30 focal deletions were observed, and many may identify potential therapeutic targets.

Potential targets in nearly 70% of tumors

Between mutation and copy number analysis, potential targets were identified in 69% of the tumors, including 42% with targets in the phosphatidyliositol-3-OH kinase/AKT/mTOR pathway and 45% with targets in the RTK/MAPK pathway (including ERBB2).

In addition, chromatin regulatory genes were more frequently mutated in urothelial carcinoma than in any other common cancer studied so far, indicating the future possibility of targeted therapy for chromatin abnormalities.

These multiple signaling and cell cycle regulatory oncogenic pathways are altered in bladder cancer and offer immediate opportunity to study different targeted therapies.

“We need carefully designed trials to leverage these data,” Dr. Rosenberg said.

When asked whether genomics was in its infancy in bladder cancer, Dr. Rosenberg said, “It’s more accurate to say we are on the verge of adolescence. We will get there if we can get drugs that target actionable mutations into clinical trials. We need to learn from the lung cancer, breast cancer, and colon cancer experience.

“This effort may provide parts of the answers on how best to treat bladder cancer. We are all very excited.”UT

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