Investigators Look to a Better Future for Patients with Bladder Cancer

Aug. 17, 2019

Manny Tuccio, a 53-year-old husband and father of three, has a striking family history of bladder cancer. His grandfather passed away from the disease in the 1980s. His father was diagnosed with it a decade later and only survived for two years.

Manny Tuccio, with his wife Nancy and son Nicholas

When Tuccio was diagnosed in 2017 with bladder cancer, however, his luck started to change because a research boom was underway at the Wilmot Cancer Institute and across the country.

In fact, Tuccio was eligible for the latest bladder cancer intervention available, in a clinical study led by Wilmot. After his tumor was removed in the operating room, surgeons immediately instilled chemotherapy through a catheter that flowed directly into the bladder area. The trial allowed doctors to evaluate this simple, post-surgical step with the drug gemcitabine in patients with low-grade bladder cancer, to find out if it would reduce a tumor recurrence. Gemcitabine costs less and has fewer side effects than other drugs that have been used in this way.

Tuccio’s physician, pioneering urologist Edward Messing, M.D., led the landmark national study. Dozens of urologic surgeons at 23 cancer centers took part, and the results showed a 34-percent reduction in cancer recurrence for patients who received the treatment.

Today, Tuccio is among those who remain free of bladder cancer. “I don’t think I would be here now,” he says, “if I had gotten bladder cancer 10 years ago.”

Edward Messing, M.D., and Jacob Gantz, M.D.

The Journal of the American Medical Association (JAMA) published Messing’s study last year and lauded it as “practice changing.” Afterward, University of Rochester Medical Center Urology resident Jacob Gantz, M.D., launched a local implementation study to create guidelines that would improve the rates of infusing gemcitabine in the operating room. As a result, rates of usage jumped from less than 40 percent to more than 80 percent — and counting.

“This success indicates that we may become a model for other institutions,” Gantz says.

As one group of scientists, led by Messing and Gantz, steers discoveries into real-world practice, another group is exploring bladder cancer at its molecular roots.

Wilmot research by Chawnshang Chang, Ph.D., Yi-Fen Lee, Ph.D., Hiroshi Miyamoto, M.D., Ph.D., and Shu-Yuan Yeh, Ph.D., is revealing new insights into what drives the disease and possible new treatment pathways.

“It has been a big year for advances in bladder cancer,” says Messing, a professor of Urology who was honored last year with a festschrift in the journal Bladder Cancerfor his lifetime of remarkable scientific achievements. “As a result of research, there’s much more hope for advanced bladder cancer and we’re also discovering smarter ways to manage lower-burden disease.”

Data and Gender Questions

Bladder cancer is one of the trickiest cancers to manage. Although most people, like Tuccio, are diagnosed with a lower-risk subtype known as non-muscle invasive cancer, two-thirds of them will still see the cancer return within five years and 88 percent of low-risk patients develop a recurrence by 15 years. This requires close monitoring throughout patients’ lives — and the surveillance is not easy. It involves invasive cystoscopy, a procedure where a small tube with a lens is inserted through the urethra into the bladder to look for new lesions. Patients experience pain and repeatedly lose valuable time to recovery.

And for the approximately 25 percent of individuals who are initially diagnosed with the more serious type of bladder cancer, which has invaded the muscle wall, more than 50 percent will develop metastatic disease and face a median survival of only about 15 months. No new widely accepted treatments have emerged for advanced, metastatic disease in decades.

For these reasons, bladder cancer represents the highest lifetime treatment cost per patient in the U.S. — a statistic that warrants a full commitment to improve outcomes, says Lee, who focuses on how to stop bladder cancer from spreading.

The Rochester region also has a higher-than-average incidence of bladder cancer. The national average is 19.5 cases per 100,000 people but within the 27 counties in upstate New York from where Wilmot draws patients, there are 27.3 cases per 100,000, according to National Cancer Institute data.

In another twist, men are three times more likely than women to get the disease.

Hiroshi Miyamoto, M.D., Ph.D., center, and his team Takuro Goto, M.D., and Yujiro Nagata, M.D., study how androgen receptor signals promote bladder cancer growth.

More than a decade ago, Chang and Miyamoto, who at the time was a research assistant professor in Chang’s laboratory, made a critical connection between the androgen receptor (AR) — which controls male hormones such as testosterone — and bladder cancer’s development and progression.

Their discovery helped to debunk some old theories about why men have a remarkably higher incidence. With smoking as a major risk factor for bladder cancer, doctors used to believe that men were diagnosed more often because more men smoked cigarettes. But that theory blew up when smoking rates soared among women and the men-to-women bladder cancer ratio stayed nearly the same. Exposure to toxins in manufacturing and industrial jobs is another risk factor. But even as more women entered the workforce, the three-to-one bladder cancer ratio didn’t budge.

Hormones: Bladder Cancer’s Fuel

With the androgen receptor gene in play, investigators began focusing on the hormonal pathways.

Chang, the George Hoyt Whipple Distinguished Professor of Pathology, Urology and Radiation Oncology, has continued to study why AR drives bladder cancer and the connection between testosterone and bladder cancer cells.

Miyamoto has also continued to show in multiple, peer-reviewed journal articles new information about how AR signals promote bladder cancer growth. A professor of Pathology and Urology and director of Genitourinary Pathology, Miyamoto established his own lab at Wilmot. His team discovered that AR is partly the reason why bladder cancer cells are often resistant to the chemotherapy drug cisplatin and to radiation treatment; they’ve also explored ways to make the cells more sensitive to chemo and radiotherapy. Another study, a clinical trial involving 162 Japanese men who had both bladder and prostate cancer, showed that androgen deprivation therapy — a standard treatment for advanced prostate cancers — might also reduce the risk of bladder cancer recurrence, especially in patients with bladder tumors that test positive for the AR biomarker.

Miyamoto recently won a $150,000 Ferring Research Institute innovation grant to focus on a key molecule regulated by the androgen receptor and related to cisplatin resistance.

Lee and Shu-Yuan Yeh bring a different perspective to the disease — with Yeh highlighting the role of the female hormone estrogen and estrogen receptors in bladder cancer.

Yeh discovered that estrogen receptor-alpha (ER-alpha) may play a protective role in the initiation of bladder cancer while estrogen receptor-beta (ER-beta) may fuel it. The yin and yang roles of estrogen, with the receptors countering each other and balancing out the ER activity, may explain why females have a lower incidence of bladder cancer than males, she says. Recently, Yeh’s lab further delineated the roles of estrogen receptors by demonstrating their involvement in tumor metastasis.

Lee has several new research developments as well. In a study published this year by the journal Scientific Reports, Lee showed how a new tool that her lab developed can help direct attention toward bladder cancer metastasis.

Lee specializes in why bladder cancer prefers certain sites for colonization away from the original tumor. She studies the tiny vesicles released from cancer cells that contain DNA and RNA and how they nurture metastasis. Her lab has identified biomarkers that can detect vesicles in lymph nodes, urine, and blood from patients who have the muscle-invasive type of bladder cancer. The goal is to understand how the vesicles and their proteins support the survival of new cancer growths — and how to interfere with that process through drug therapy.

Lee is in the final stages of negotiating a two-year grant for $600,000 to begin on Sept. 1. The funds will support vesicle investigations as well as how cigarette smoke and flavored e-cigarettes may impact vesicle activity.

Lee also studies the mechanics behind Bacillus Calmette-Guerin, an immunotherapy treatment for early stage bladder cancer. BCG is derived from a weak strain of a bacteria used in the vaccine against tuberculosis; it is usually injected directly into the bladder. Her team is investigating why some patients don’t respond to BCG treatment and they’re searching for biomarkers that predict treatment response.

Chang, in a separate investigation, also discovered that BCG plus anti-androgen therapy was more effective than BCG alone in destroying bladder cancer cells.

“We’re on our way to becoming a bladder cancer destination center,” Messing says. “Right now, we’re scratching the surface on so many developments and we have more things to pursue in the future, including the role of the microbiome (gut bacteria) and its influence on treatment, and improvements in immunotherapy.”

Meanwhile, Messing adds, the U.S. Food and Drug Administration approved five immunotherapy drugs for bladder cancer in the past couple of years, providing options for patients as bench science continues to churn.

‘Changing the Mindset’

Gantz, the Urology resident who works with Messing, is devoted to speeding up the time it takes to bring new treatments to patient care.

He conducted a further analysis of Messing’s gemcitabine study, for example, to uncover what types of logistical barriers might prevent surgeons from using the new approach in the operating room.

Is it training, insurance issues, or perceived inconvenience? An older chemotherapy drug that had been similarly used years ago was much more expensive and came with a lot of side effects — casting a dark cloud over the idea of instilling any type of chemotherapy in the operating room, Gantz says.

But he was undeterred. Funded by a small grant from the Urological Care Foundation, in just six months Gantz gathered data and spoke to attending physicians, residents, pharmacists, operating room schedulers, operating room nurses, anesthesia specialists, and staff. He educated the group on the benefits shown by the new study. The team created an automated report in the URMC electronic medical record system with a streamlined way to order gemcitabine into the operating room. He even hung posters in the ORs and urology clinics.

“It’s about changing the mindset,” Gantz says. “If you encourage people and point out how things can be different, it can change. Eventually, people understand this is worth pursuing.”

Gantz’s study is largely responsible for the soaring new rates of gemcitabine usage for eligible bladder cancer patients, based on Messing’s groundbreaking protocols.

“This is medical innovation,” Gantz says, “and the whole point is to take these discoveries and make them work for our patients.”