Bladder cancer is the fifth most common form of cancer overall and the fourth most common among men. Although treatments are typically effective if the disease is detected early, many people are diagnosed after the tumor has grown into the bladder wall or beyond. In this situation, the bladder often must be removed, which can significantly affect a person’s quality of life.
Doctors and researchers at Memorial Sloan Kettering are hoping to change the outlook for many people with the disease. The key is gaining new insights into how various genetic changes and molecular characteristics affect the way bladder cancers develop and respond to treatment. This effort received a boost in October 2018 when the National Cancer Institute awarded MSK a prestigious SPORE (Specialized Programs of Research Excellence) grant for bladder cancer.
SPOREs are designed to speed the movement of basic scientific findings into patient care. The grants require each scientific project to reach clinical testing by the end of the five-year funding period. MSK’s $6.5 million grant, the only active SPORE for bladder cancer, is co-led by medical oncologists Dean Bajorin and David Solit.
“There’s a palpable excitement in the cancer community that we are on the cusp of major advances in how to treat bladder cancer,” Dr. Bajorin says. “SPORE grants really encourage bringing the best science into the clinical realm, and MSK has such a breadth of research. We have experts in genetics, molecular oncology, and immunology who can work closely to produce insights that advance the field.”
MSK’s bladder cancer SPORE is organized around four projects. Each project is headed by basic and clinical investigators who work together to address a specific aspect of the disease. The projects have their own co-leaders, but the researchers for all of the projects constantly collaborate.
“The projects are very synergistic,” Dr. Solit says. “The SPORE brings together a team of experts in different fields to make the overall research effort stronger. We have regular meetings as a joint group to discuss preliminary results. The data we generate in different contexts can be merged together, which helps each of the projects move forward faster.”
“A Fascinating Tumor”
The SPORE also provides funds for young investigators. In addition, the funding for promising new projects could attract experts in other fields to bladder cancer research.
“It’s become a fascinating tumor for people to study,” Dr. Bajorin says. “We have people who were not previously interested in bladder cancer who now want to be involved. We’re getting more people on board, and the SPORE encourages that.”
Avoiding Bladder Removal
One project, led by Dr. Solit and medical oncologist Gopa Iyer, investigates whether people whose bladder cancer is muscle invasive, meaning it has grown into the wall of the bladder, can avoid having their bladder removed. Some people have bladder tumors with genetic changes called DNA-damage response (DDR) mutations. Research has shown that these people usually respond especially well to chemotherapy before surgery.
A clinical trial will test whether these patients can be given chemotherapy and then have their tumor removed through the urethra with a cystoscope (a thin, lighted instrument). This will leave the rest of the bladder intact. The patients will then be closely monitored, with examinations by cystoscope and radiology scans every few months.
“Taking out the whole bladder can significantly impact a person’s quality of life, and we believe that genetic analysis of the tumor can tell us who does not need to undergo that type of surgery,” says Dr. Solit. “We will also try to figure out why some people without DDR mutations respond well to chemotherapy. If we can identify additional mutations or other biomarkers that predict for sensitivity to chemotherapy, more people could be eligible for this bladder-sparing approach.”Back to top
Shedding Light on Inherited Risk
A second project is trying to identify inherited, or germline, genetic mutations that increase the risk of developing bladder cancer. It is being led by Dr. Bajorin; Kenneth Offit, Chief of MSK’s Clinical Genetics Service; and molecular biologist John Petrini. Some germline mutations are already known to increase bladder cancer risk, including the BRCA genes, which are notably associated with breast and ovarian cancer. But there is strong evidence suggesting that there are additional germline mutations associated with an increased likelihood of developing a cancer. The researchers are sequencing germline DNA from people in families prone to bladder cancer. They also are looking at DNA from people diagnosed with bladder cancer at an early age and people who have bladder cancer along with multiple other cancers.
If additional mutations are found, Dr. Petrini’s lab will conduct laboratory experiments to confirm that these mutations actually contribute to the development of cancer.Back to top
Predicting Response to Immunotherapy
Another project, led by physician-scientist Timothy Chan and medical oncologist Jonathan Rosenberg, seeks to understand what causes bladder cancer to respond to or resist the immunotherapy drugs called checkpoint inhibitors. Five checkpoint inhibitors have been approved by the US Food and Drug Administration for bladder cancer in the last three years. These drugs work for only a small number of people, however. And just one, atezolizumab (Tencentriq®), is approved for people whose disease has progressed after chemotherapy. Only 24% of people with bladder cancer respond to atezolizumab.
A multicenter clinical trial will test atezolizumab in combination with bevacizumab (Avastin®). Bevacizumab blocks the growth of a tumor’s blood vessels and can improve the effectiveness of checkpoint inhibitors.
“It was recently shown that this combination works quite well in kidney cancer that has spread, or metastasized, and we have data suggesting that it could work against metastatic bladder cancer,” Dr. Bajorin says. “The question is, how beneficial is it? Within the context of the SPORE project, we will study blood and tumor samples collected during the trial to look for biologic reasons why someone may or may not respond to this combination. These studies may suggest new strategies for patients whose tumors do not benefit from current immunotherapy treatments.”Back to top
A Better BCG Therapy
The fourth project will seek to understand and improve another form of immunotherapy: BCG (Bacillus Calmette-Guérin). This treatment is a weakened form of a bacterial pathogen. It has been used for noninvasive bladder cancer for more than 50 years. The study is being led by physician-scientist Michael Glickman, infectious disease specialist Gil-Redelman Sidi, and urologic surgeon Bernard Bochner.
BCG causes inflammation and appears to stimulate the immune system to attack bladder cancer cells. MSK researchers have found evidence that the treatment’s effectiveness may be determined partly by the presence of specific genetic mutations within cancer cells. But exactly how BCG works is still not clear, including which part of the interaction between the cancer cells and surrounding normal and immune cells is most important for the treatment to work. Dr. Glickman’s lab has created various strains of BCG to improve its effectiveness.
“We’ve been using BCG for a long time, but it might not be the best type of BCG,” Dr. Bajorin says. “An enhanced form of BCG, optimized to induce a vigorous immune response against a person’s specific cancer, may offer better long-term treatment. A longer-term goal is to test these new strains of BCG alone initially, then in combination with checkpoint blockade.” This novel BCG research is critical to all MSK patients, given the repeated intermittent shortages of BCG worldwide.