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CU Cancer Center Researcher Among Team Investigating Bladder Cancer That Doesn’t Respond to Treatment 

James Costello, PhD, is co-author on a new study that may allow doctors to identify non-muscle invasive bladder cancer that is not likely to respond to BCG immunotherapy. 

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Written by Greg Glasgow on July 12, 2023

Research that began at the University of Colorado Cancer Center may help doctors better treat patients with non-muscle invasive bladder cancer.  

“Bladder cancer comes in two major forms, muscle invasive and non-muscle invasive,” says University of Colorado Cancer Center member James Costello, PhD, one of the authors on the study. “Muscle invasive is the one you think of when you think of bladder cancer, where treatment can include chemotherapy, immunotherapy, or surgery. Non-muscle invasive bladder cancer tumors are like warts that grow on the inside of the bladder. A standard approach in this setting is to treat with BCG (Bacille Calmette-Guérin), which is a tuberculosis vaccine that causes a localized immune response to help your body attack the tumors. However, not all tumors respond well to BCG and we currently don’t know for which patients the treatment will work well or not.”

When treatment makes things worse 

Costello and his fellow researchers wanted to understand why some non-muscle invasive bladder cancer doesn’t respond to standard treatment. Using a collection of more than 300 patient samples, they found that not only do some tumors not respond to the first-line treatment, but in some cases the treatment made the cancer more aggressive.  

“When we give patients treatment, there will be tumors that respond, and there will be tumors that do not respond,” says Costello, associate professor of pharmacology in the CU School of Medicine. “Typically, the ones that do not respond have some type of resistance mechanism to the treatment, which means you are basically selecting for a more aggressive tumor with treatment. If you treat a patient’s cancer and it does not respond or even progresses on therapy, it suggests that their tumors are inherently more primed to become aggressive. Non-muscle invasive bladder cancer can progress to metastatic quickly in the right setting.”

The first-line treatment for non-muscle invasive bladder cancer is transurethral surgery — a surgery performed through the urethra — to remove the tumors. If recurrence of tumors occurs, these tumors will be again be removed by transurethral surgery with the option to be followed with BCG treatment.

“Some cancers respond great to BCG, and some do not respond very well,” Costello says. “And a lot of times the tumors that don't respond or have recurrence on BCG treatment are more likely to progress into an aggressive state. We really wanted to understand, ‘Which non-muscle invasive bladder cancers are predisposed to not respond to BCG treatment?’ because if we give BCG treatment and drive these tumors to a more aggressive state, then we are making the situation worse for the patient.”

Indicators of non-response 

Published in May in the journal Science Translational Medicine, the team’s study found a diagnostic molecular profile that predicts a patient’s response to BCG. Using that as a tool, oncologists could now biopsy a non-muscle invasive bladder cancer tumor and use this information to recommend alternative therapies for patients whose cancer is not likely to respond to BCG.

“Maybe the best treatment option is to perform a radical cystectomy, or removal of the bladder, or try intravesical chemotherapy or some other kind of treatment options,” Costello says. “It gives the oncologist more information about the likelihood of response, which can help them make decisions in the best interest of their patient.”

Costello stresses that this was an initial study. The next step would be to do a similar study on a larger group of patients who are not responsive to BCG treatment, as well as a clinical trial of the molecular diagnostic.

“Building off of this research, we're also developing a larger international working group around non-muscle invasive bladder cancer, joining with other groups that have done similar studies,” he says. “We want to compare tumors that are truly benign and in a very early stage to those that are higher risk and see what the differences are. What are the molecular features that potentially drive tumors into these different states? What are the molecular features associated with tumor non-response? There are many more questions and a need for further validation of this predictive signature to different forms of non-muscle invasive bladder cancers.”

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James Costello, PhD