Study Clarifies How Bladder Cancer Treatment Works

Pictured: BCG

Bladder cancer cells infected with BCG (shown in green), an effective treatment for early-stage bladder cancer. The same genetic mutations that cause bladder cancer also activate a mechanism in the cells that allows BCG to enter and destroy them.

Memorial Sloan Kettering researchers have shed light on how an important treatment for early-stage bladder cancer eradicates cancer cells. They also found evidence that the effectiveness of this bacterial treatment, called BCG therapy, may be determined partly by the presence of specific genetic mutations within cancer cells.

“This study shows that some of the same mutations causing bladder cancer also activate a process that allows the treatment to enter the cancer cells and destroy them,” says Gil Redelman-Sidi, an infectious diseases specialist who conducted the research together with physician-scientist Michael S. Glickman. “It raises the possibility that specific properties of a patient’s tumor cells might predict how well BCG therapy will work.”

The researchers, including Memorial Sloan Kettering physician-scientists and co-authors David B. Solit and Gopa Iyer, report this finding in the February 1 issue of Cancer Research.

Effective, But Mysterious

BCG (Bacillus Calmette-Guerin) is a weakened form of a bacterial pathogen that has been used widely as a vaccine for tuberculosis for nearly a century. Beginning in the 1950s, the late Memorial Sloan Kettering cancer immunologist Lloyd J. Old and other researchers began investigating BCG as a treatment for cancer, and clinical studies conducted at Memorial Sloan Kettering demonstrated the effectiveness of this therapy for early-stage bladder cancer.

Although BCG continues to be the preferred treatment for such cancers, it has not been clear how the pathogen invades the cancer cells and — once inside — leads to their destruction. Many researchers think BCG stimulates some form of antitumor immunity, but the exact mechanism has not been well understood. To add to the puzzle, approximately 30 percent of bladder cancer patients don’t respond to BCG treatment, and no test exists to predict which patients will be resistant.

“BCG is a mycobacterium — a type of bacteria usually taken in only by certain immune cells that are looking for invaders to destroy,” Dr. Glickman explains. “Mycobacteria are not equipped with a means to force their way into other kinds of cells, so it has been a bit of a mystery how BCG enters bladder cancer cells and why certain cells resist the treatment.”

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Mutations Open the Door

An important insight into what makes the entry of BCG into cells possible arose from a collaboration between the Glickman lab and Memorial Sloan Kettering cell biologist Xuejun Jiang. In June 2012, this team reported in the Journal of Biological Chemistry that cancer cells with mutations in the gene PTEN are highly susceptible to mycobacterial infection. The PTEN protein normally acts as a tumor suppressor; impaired PTEN function appears to increase a cell’s vulnerability to becoming cancerous and also to mycobacterial infection.

To investigate whether this correlation holds true in bladder cancer cells, Drs. Redelman-Sidi, Glickman, and colleagues treated six distinct cell lines — groups of genetically identical cells developed from a single cell — with BCG and measured the degree to which the BCG bacterium was taken up by the cells.

They discovered that the cell lines that most readily took up BCG contained one of several cancer-causing mutations, including mutations in PTEN, known to be involved in the onset of bladder cancer. The cell lines resistant to BCG did not have these particular mutations, but they could be converted to BCG-receptive cells if the mutations were induced. Moreover, these converted cells readily took up BCG via a pathway different from the one BCG usually employs to enter immune cells.

“These mutations activate a mechanism in the bladder cancer cells that allows BCG to enter and destroy them,” Dr. Glickman says.

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Moving from the Lab to the Clinic

Dr. Glickman’s laboratory is now collaborating with urologic surgeon Bernard H. Bochner to explore the clinical implications of this discovery — particularly, whether analyzing a patient’s bladder cancer cells can reliably predict his or her responsiveness to BCG therapy.

With the support of a grant from The Society of MSKCC, Dr. Redelman-Sidi is trying to develop a lab test that would analyze urine samples, which usually contain cancer cells shed from the bladder. These cells could be tested both for their tendency to take up BCG and also for the presence of BCG-activating, cancer-causing mutations.

“This would allow us to screen early-stage patients routinely before starting BCG therapy to make sure it’s the best course of treatment,” Dr. Glickman says.

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Dr. Redelman-Sidi’s work is supported by awards from the Lucille Castori Center for Microbes, Inflammation, and Cancer and from the Bladder Cancer Advocacy Network. The study reported in Cancer Research was supported by the Geoffrey Beene Cancer Research Center and the Starr Foundation.