Discovery
January 01, 2017

Never has there been so much hope and excitement in the field of bladder cancer research and treatment, and the Greenberg Institute is right at the forefront. Gene-based approaches are creating smarter, more targeted treatments. New immunotherapy drugs are curing cancers that even a few years ago proved deadly. Brady scientists stand at the brink of a revolution in restorative surgery — creating entirely new replacement bladders out of a patient’s own tissue and stem cells. And we are excited to tell you that after an international search, the Institute has its first Director: David McConkey, Ph.D.

So many advances, and so much to look forward to — not bad at all for one of the world’s lowest-funded and most notoriously under-investigated diseases. In fact, it was this great need to find scientific answers and develop better treatment for what has been called the “invisible cancer” that led Baltimore philanthropists Stephanie Cooper Greenberg and Erwin L. Greenberg last year to commit $15 million, with a $30 million co-investment from The Johns Hopkins University, to start the Greenberg Bladder Cancer Institute — the first of its kind in the world.

McConkey comes to the Brady from the University of Texas M.D. Anderson Cancer Center, where he was the Director of Urological Research and Professor of Urology. 

Molecular subtypes: McConkey is part of a group of scientists working together on bladder cancer from around the world. Over the last few years, they have noticed some important similarities between bladder cancer and breast cancer. “We discovered that muscle-invasive bladder cancers can be grouped into subtypes of basal and luminal tumors that resemble the ones found in breast cancers,” says McConkey. These cancers behave differently: “Like their breast cancer counterparts, basal bladder cancers are more aggressive, and are associated with early metastasis and death in patients who do not receive cisplatin-based chemotherapy.” But there is good news for people with these cancers: “We discovered that patients with basal cancers who receive neoadjuvant chemotherapy actually have excellent long-term outcomes.” McConkey and colleagues recently published these findings in European Urology. If the results of their study are confirmed, “this should prompt clinicians to be more aggressive in offering presurgical chemotherapy to all patients who have these potentially lethal basal bladder cancers.”

Gene-targeted treatment and immunotherapy: The bladder has a unique advantage when it comes to cancer treatment: “The organ is confined,” says McConkey, “and we can exploit that.” For years now, urologists have been using BCG (bacilli Calmette-Guerin), a form of bacteria used in the tuberculosis vaccine, to treat some noninvasive bladder cancers. BCG, delivered directly into the bladder through a catheter, stimulates the immune system to fight off cancer cells. Sometimes it is used in combination with another immunotherapy drug called interferon alpha 2b. “In many cancers, delivery is a major problem. But we are putting people into long- term remission, and there are many possibilities for gene editing and gene transfer,” fixing a mutated gene by switching it with an undamaged one. Physician-scientist Colin Dinney, M.D., Chairman of Urology at MD Anderson, is investigating another form of interferon gene therapy using an adenovirus (the virus found in the common cold).

Exciting new immunotherapy drugs called “checkpoint inhibitors” are achieving results considered miraculous in many forms of advanced cancer. Several newly available drugs target specific proteins that fool the immune system into thinking cancer is not an enemy: when these proteins are blocked, the immune system recognizes tumor cells and attacks them, in many cases causing tumors to melt away. In bladder cancer, however, the optimal genetic warrior drug has not yet been found; McConkey, Noah Hahn, M.D., and colleagues at MD Anderson believe a molecule called fibroblast growth factor receptor 3 (FGFR3) is a promising target, and they have received an innovation award from the Bladder Cancer Advocacy Network (BCAN) to study it. “In bladder cancer, lymphocytes” — disease-fighting white blood cells — are not able to penetrate the tumors very well,” he says. But blocking FGFR3 may open the door for lymphocytes to elbow their way into bladder tumors and start killing cancer cells.

Better reconstruction: “Tissue engineering is the ultimate in reconstruction,” says McConkey, “and we have assembled a fantastic team to create a new bladder out of a patient’s own cells. Layering stem cells and similarly plastic cells called progenitor cells around a scaffold, Brady and colleagues are “doing 3-D chemistry.” Getting these cells to take their proper places on the scaffold has been a huge challenge, “but Trinity solved it.” If this work proves successful, one day instead of crafting a neobladder out of bowel tissue, surgeons will simply remove the old bladder and put in a brand new one.

Raising the profile: Bladder cancer has long ranked near the bottom in research money spent, despite the number of people who have it, says McConkey. “It’s important to get the word out, not just to help support NIH investment in bladder cancer research, but also to help the public understand what a significant health problem it is.” Cigarette smoking is the biggest risk factor, but there is no targeted screening. “Although people with a history of smoking have a much higher risk, many doctors don’t connect those dots right away.” The other part of the low-profile problem is that “people who are diagnosed just don’t want to talk about it,” although that’s changing with the help of BCAN, he adds. Also changing is the momentum in developing new forms of treatment. Until the recent success of checkpoint inhibitors, “pharmaceutical companies weren’t all that interested in developing clinical trials in bladder cancer. Now they are,” and with better surgery and new genetic strategies, “we’re experiencing a perfect storm that is leading to rapid progress.