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New Hope for Bladder Cancer Patients

Cancer Center researchers.

A bladder cancer drug discovered and developed at The University of Kansas Cancer Center is set to become its first cancer drug to go from bench to bedside.

The University of Kansas Cancer Center’s nationally recognized proof-of-concept center and product development arm, the Institute for Advancing Medical Innovation (IAMI), translates laboratory and bedside discoveries into new drugs, diagnostic tests and medical devices with the goal of advancing promising medical innovations to patients. Simply put, IAMI works with cancer center and other National Cancer Institute-designated centers to develop medical innovations that change the standard of cancer care. Through a research effort led by IAMI, patients with bladder cancer may finally have a new treatment option. More than 2 decades have passed since a new therapy has been introduced.

Bladder cancer is the 5th most common cancer in the United States, with approximately 77,000 new cases and 16,000 deaths annually. It has the highest recurrence rate among all cancers – up to 50% of cases may recur within 12 months. Additionally, 25% may advance to muscle invasive disease, requiring more aggressive treatment. As such, patients face a lifetime of monitoring and medical care.

Standard care for nonmuscle invasive disease is surgical removal of the tumor and possible administration of chemotherapy or immunotherapy directly into the bladder. While effective for most patients, some cases may not respond, develop intolerance, or recur during treatment.

Giving an old drug a new purpose

Ciclopirox was first marketed in 1982 as an antifungal agent found in several topical drug products. The University of Kansas Cancer Center researchers began working on ciclopirox through a collaboration with The Leukemia and Lymphoma Society and Ontario Cancer Institute as a potential treatment for acute myeloid leukemia (AML). However, a clinical trial demonstrated that ciclopirox, given orally, was not a viable treatment.

Researchers Scott Weir, PharmD, PhD, director of IAMI, and Shrikant Anant, PhD, associate director for cancer prevention and control research program, decided to modify the drug to be administered intravenously. The new drug, called Ciclopirox Prodrug, converted to ciclopirox in the bloodstream where it then was selectively delivered to the urinary tract. Further research demonstrated that it was able to kill bladder cancer cells.

Following these promising findings, Anant and Weir recruited renowned bladder cancer expert John Taylor III, MD, MS, professor of urology at the University of Kansas School of Medicine, whose lab has extensive experience in bladder cancer modeling, as well as the ideal mouse model in which to test the drug.

The outcome?

“Fantastic results. Not only did the drug have an effect on the cancer cells, but it did not harm surrounding healthy cells,” Anant said.

Anant, Taylor and Weir demonstrated in animals that giving Ciclopirox Prodrug by injection selectively delivers the active anticancer agent, ciclopirox, to the entire urinary tract. At well-tolerated doses administered intravenously and by injection, urinary tract concentrations of the active agent are achieved that exceed those required to kill bladder cancer cells in the test tube by several fold.

“This is potentially a game-changer in treating patients with noninvasive bladder cancer. A new and effective drug, which doesn’t require catheterization, is welcomed in a field where care has not advanced much in several decades,” Taylor said.

Because the Food and Drug Administration (FDA) requires extensive resources to demonstrate that a drug is a viable treatment for patients, academic institutions often partner with the private sector to advance the drug to a clinical trial. Under an existing partnership agreement, the University of Kansas Medical Center licensed Ciclopirox Prodrug to BioNovus Innovations LLS. Development is being managed by BioNovus subsidiary CicloMed LLC. This is the first product development and commercialization collaboration between BioNovus and IAMI.

CicloMed is on track to submit an investigational new drug (IND) application to the FDA in early 2017. Pending FDA clearance, the firm intends to initiate a Phase I clinical trial at several sites, including The University of Kansas Cancer Center. The goal is to enroll the first patient in a clinical trial by mid-2017.

“It takes a village to understand the biology of cancer, discover and develop new cancer treatments and demonstrate that the treatment is effective," Weir said. “We’re proud to have built a team of experts whose strengths span the spectrum of research – from basic to translational to clinical. Because of this team effort, bladder cancer patients may soon have better treatment options.”

Bench to Bedside: Innovations in Bladder Cancer

Scott Weir, PharmD, PhD, and John Taylor, MD, MS, discuss the latest in bladder cancer research and treatment.

Speaker 1: Welcome to Bench to Bedside, a weekly series of live conversations about recent advances in cancer from the research bench to treatment at the patient's bedside. And now your host and the director of the University of Kansas Cancer Center, Dr. Roy Jensen.

Dr. Shrikant A.: Good morning. I'm Dr. Shrikant Anant and I'm sitting for Dr. Roy Jensen. Thanks for joining us for today's episode of Bench to Bedside. Today we have two amazing scientists. First one I'd like to introduce to you on my left is Dr. John Taylor, he's the Director of Basic Urology Research and he's also the Co-leader of the University of Kansas Cancer Center's Drug Discovery Program. And then we have Dr. Scott Weir, he is the Director of the Institute for Advancing Medical Innovations, a tongue twister I should say, for the University of Kansas Medical Center and he's also the Associate Director for the University of Kansas Cancer Center. And really involved in drug discovery and transmitting it to the patients. Today we are focusing our discussion on the latest in bladder cancer research and treatment. I want to also let you know that we have Alicia Miller who is here in the studio, and she's waiting to get as many questions from the audience as possible, so that we can give that to experts here who can answer those questions for you. Let me start with you, Dr. Taylor. John, tell me about bladder cancer. Tell us what does it mean to say that somebody has bladder cancer?

Dr. John Taylor: Shri, I think you've heard me say in the past bladder cancer is the black sheep of cancers. It's a very common disease that is under recognized on the national and international front., it's the fifth most common solid tumor in the United States. About 80,000 cases are diagnosed each year, and it amazes me when patients come in with bladder cancer that they've not heard of it, it's not something they're aware of. But bladder is the organ that allows us to be socially acceptable and hold our urine until it's time to expel it. It is a very important organ and we can't live without it.

Dr. Shrikant A.: Tell me, so 80,000 patients, how long do they live with this cancer really when they get it?

Dr. John Taylor: It all depends on the stage of presentation, so how advanced the cancer goes when the patient presents. Fortunately, the majority of patients will present with an early stage cancer and the survival overall is very good. I think we're looking at five year survivals for all stages of cancer, so from the earliest to the most advanced. We're looking at anywhere from 70 to 90%, 70 to 90% five year survival rates.

Dr. Shrikant A.: That's a long survival, and some of these patients live for 30, 40 years then?

Dr. John Taylor: A very long time.

Dr. Shrikant A.: Wow.

Dr. John Taylor: So patients with the earlier stage cancers, they can live 30, 40 years but they're at risk for high rates of recurrence of the disease, and that's what makes it one of the most expensive cancers to treat.

Dr. Shrikant A.: You came up with the most important second question, what are the risk factors that puts you are at high risk for bladder cancer?

Dr. John Taylor: Smoking, smoking, smoking, and then exposure. We call it a disease of exposure, there are no known genetic risk factors for it. There are some in question but by most parts is considered a disease of exposure. Smoking is the number one risk factor, about a 60 plus percent of all cancers are directly causally related to smoking. Then we look at environmental and occupational exposure to other carcinogens and there's a whole laundry list of them that are out there. Interestingly, the Department of Defense has recently recognized that soldiers exposed to defoliants in Vietnam, so typical Agent Orange, Agent Blue, may be an increased risk to bladder cancer due to some of the chemicals that were found in those defoliants.

Dr. Shrikant A.: That brings up an important question. All these veterans who have potentially been exposed to these things, is the VA doing something about ensuring that they are not ... Are they being monitored? How does bladder cancer get detected and how do you currently treat them?

Dr. John Taylor: Let me back up to your first question, which is the DoD. We were very excited several years ago when the initiative was brought forth because those of us in the field felt that we were not getting a fair shake at some of the research money that was out there. The DoD opened up their major research program-

Dr. Shrikant A.: Let me start there, DoD is Department of Defense.

Dr. John Taylor: Department of Defense, sure. The Department of Defense opened up their research program to bladder cancer about three or four years ago, and it's been wonderful to have access to some of those funds. They have recognized that they are beginning to make inroads into supporting research which is critical to advancing care for patients in this field. Your second question regarding detection, bladder cancer is unique amongst cancers and that it's not typically detected at autopsy, so it's not something that's incidentally found when people pass. It's almost always found during the patient's lifetime and is found about 80% of the time with visible blood or microscopic blood in the urine. Then, importantly, at about 20% of the time patients can present with new onset of urinary symptoms: urgency, frequency, discomfort in the pelvis, and we have to be attuned to that. Because of that and because of the similarities to other symptoms that people will experience as they age, many patients experience a delay in diagnosis particularly women due to coincident findings such that would be presently infections, or just urgency frequency with urination with aging.

Dr. Shrikant A.: Do they have been burning sensation or anything like that?

Dr. John Taylor: Not typically, so the other common symptoms of a urinary tract infection are absent, and that's what makes-

Dr. Shrikant A.: That's how you differentiate.

Dr. John Taylor: So we call it painless blood in the urine, so not associated with other symptoms.

Dr. Shrikant A.: Okay, thank you. If you're just joining us, we are here with Dr. Scott Weir and Dr. John Taylor, and we're talking about the latest in bladder cancer research. Remember, Alicia Miller's here in the studio to take your questions and we're waiting to get your questions. Please, also share this link with people you might think have the benefit with our discussion. Maybe they can join in and then ask questions. Please, definitely, use the hashtag Bench to Bedside. Let me tell my question to you Dr. Weir. In your role as the KU Cancer Center in Advancing Drugs, your focus on the Bench to Bedside, can you tell us a little bit about the drug that you have discovered for bladder cancer?

Dr. John Taylor: Sure Shri, and by the way, the drug discovered is it was discovered by a team here at the University of Kansas Cancer Center of which you are both a part. Ciclopirox Prodrug is a promising treatment discovered in our laboratories for the treatment of non-muscle invasive and muscle invasive bladder cancer. It represents the first KU invented cancer drug that we've advanced from the bench to the bedside.

Dr. Shrikant A.: Let me just turn back to you. What kind of drugs are used for the early stages of bladder cancer? Is there one?

Dr. John Taylor: I've got to throw in a little bit more into your answer because I think there's important things to understand about bladder cancer, which are concerning to those of us in the field but also we're in an exciting time. Bladder cancer weather is in early stages or late stages has not seen a novel or new treatment in decades. For non-invasive, so for early stage cancers that are not invading the wall of the bladder, we're using immunotherapeutic called BCG, which is placed into the bladder to incite an immune response. And that's been around since the '70s. For more advanced bladder cancer where we actually have to remove the bladder, we're doing what's called a cecectomy, which is removing the bladder. It's one of the biggest operations that we can do and it's got a high risk of complications. Now, I should say that my grandmother had a cecectomy in 1960, and I like to give introductions, when I give presentations outside the university that my grandmother would roll over in her grave knowing that her grandson is doing the same operation 60 years later, almost 60 years later from when she had her operation. We haven't made a lot of inroads in it, that's one problem. We're beginning to see a lot of inroads into this area in today's world and Ciclopirox is an example of that.

Dr. Shrikant A.: It sounds to me like Ciclopirox is a really awesome new development that has happened in the recent past?

Dr. John Taylor: Absolutely, if we can introduce any novel agent that can, A, act in a or have better results than we typically see with other drugs or other treatments, or if we can have a new agent that could be administered differently. For people that have bladder cancer that's in early stages, they have to come into the office once a week for six weeks, and then every three weeks at various time points to have a catheter put in and have an agent put in their bladder and then have to hold that. If we could find a novel agent that's not administered in that way, either intravenously or orally or some other route, that would be earth shattering to the field.

Dr. Shrikant A.: You mean that if I had bladder cancer, I could be at home and just take a pill or have a nurse come and just give me an injection like a diabetic patient does potentially?

Dr. John Taylor: Right, for some of the agents that are being developed-

Dr. Shrikant A.: That would be awesome.

Dr. John Taylor: ... including Ciclopirox, it would be revolutionary to the flock, yeah.

Dr. Shrikant A.: Wow, so where are we with this drug?

Dr. Scott Weir: The work that we completed within the university was we demonstrated that Ciclopirox Prodrug kills bladder cancer cells in the test tube. We also showed that it is effective in treating bladder cancer in mice and based. Then we also were able to figure out how to manufacture the drug and formulate it into an injectable drug product much like as you said, Shri, a diabetic would inject insulin. Then with that we partnered with a biotech company here in Kansas City called CicloMed, and together we completed the studies required by the Food and Drug Administration-

Dr. Shrikant A.: FDA.

Dr. Scott Weir: ... to be able to advance this drug from our laboratories to patients. We completed that work, received clearance from the FDA in the fall of last year, and we're currently evaluating the safety of Ciclopirox Prodrug in cancer patients at four sites across the US.

Dr. John Taylor: So, Shri, I got to interject and say one other thing about Ciclopirox or a drug that would be administered that would get into the circulation and be cleared in the urine. One of the interesting things or novel things about Ciclopirox is that it winds up in the urine in high concentrations. As I talked about treating bladder cancer, putting a catheter into the bladder and treating the bladder, you can get the same types of tumors in the lining of the kidneys and the tubes between the kidneys and the bladder, the ureters, on down. Those are far more difficult to treat because of gaining access to them. If we had a compound or a drug that was-

Dr. Shrikant A.: Let me just stop you there for a split second. What you're saying is now we give them BCG where you take a catheter and you put it into the bladder. But the BCG cannot quite make it up to the tube that connects between the kidney and the bladder, and so this cancer can also be in that spot. If that happens, then all bets are off, the BCG never makes it there.

Dr. John Taylor: Exactly, there are ways to get the BCG into the upper tracks is what we call them, between the kidney and bladder. But it's a little bit more complicated, it's a little bit more difficult, and the advocacy is not-

Dr. Shrikant A.: The patient suffers through all of this.

Dr. John Taylor: And the patient has to deal with all of this. It's something that could treat the upper tracks, the kidney lining, and the tube lining between the kidney and the bladder as well as treat the bladder again-

Dr. Shrikant A.: Without making cuts and incisions and catheters-

Dr. John Taylor: ... without having to put catheters or anything else like that would be dramatic.

Dr. Shrikant A.: What is the records rate for patients who get BCG?

Dr. John Taylor: We still look at recurrence rates for the early stage diseases. We look at five year recurrence rates can be as anywhere from 40 to 70% depending on-

Dr. Shrikant A.: 40 to 70.

Dr. John Taylor: 40 to 70%.

Dr. Shrikant A.: That means pretty much almost one in two patients back in the doctor's office because they have records.

Dr. John Taylor: Exactly, and that's why we go back to being one of the most expensive cancers to treat over the lifetime of the patient is due to the need for surveillance. Additional multiple treatments for occurrences and if the tumor progresses, if it advances into an advanced stage, then they are subject to the major operations that we talked about.

Dr. Shrikant A.: So then Medicare is going to be really happy if a drug like this comes out?

Dr. John Taylor: Patients will be really happy if a drug like this come out.

Dr. Shrikant A.: Patients will be happy-

Dr. John Taylor: Yeah, absolutely.

Dr. Shrikant A.: ... but so will the medical organizations that have been subsidizing this.

Dr. Scott Weir: If I can add based on how we believe this drug works to kill bladder cancer cells, our vision for this drug is it would be given in combination with standard of care therapy-

Dr. Shrikant A.: To begin with.

Dr. Scott Weir: ... to reduce the recurrence of bladder cancer in patients who are at high risk.

Dr. Shrikant A.: So that you can reduce the side effects of the drugs from the ... In addition to the fact that you can treat the ones in the upper track, what are the side effects of BCG? Is that really morbid for the patient and-

Dr. John Taylor: No, BCG is not some morbid, it's most of the symptoms patient experience from that are what we call local symptoms or irritated symptoms. Increased urgency of urination, burning with urination, possibly some blood in the urine. The treatments are not horrible, but if you talk to patients that have them-

Dr. Shrikant A.: I wouldn't want it.

Dr. John Taylor: Absolutely, yeah.

Dr. Shrikant A.: That sounds right.

Dr. John Taylor: If you give a patient a choice of having a catheter and something like BCG put in the bladder versus taking a pill or having something infused in the vein or some other form, I guarantee you they'd all line up for the latter.

Dr. Shrikant A.: Yeah, congratulations, guys. This is really a major achievement. When do you think this would get to the patients?

Dr. Scott Weir: Well, we're evaluating the safety of this drug in cancer patients currently and our plans are to expand this clinical trial to begin evaluating its activity in bladder cancer patients next year.

Dr. Shrikant A.: Great. Okay, in case you're just joining us, we're talking about bladder cancer, and Alicia Miller is here to take your questions, which I can then ... she can then ask us and the experts here can tell you the answers to that. Alicia, do we have a question?

Alicia Miller: Yes, we do. The first question is where are you in the process of making Ciclopirox available to patients?

Dr. Shrikant A.: We just talked about that. Scott, do you want to answer that again so they can hear it?

Dr. Scott Weir: Sure. We're currently evaluating the safety of Ciclopirox Prodrug in cancer patients in our first, who are participating, in our first in human trial that's being conducted at four clinics sites across the US. Then our plans are to expand this trial next year to begin evaluating it in bladder cancer patients.

Dr. Shrikant A.: When you get this done, you go back to the FDA, you show them the data, and then they say go, no go, to the next step?

Dr. Scott Weir: Correct. The process is we will collect all the safety data from the ongoing clinical trial, we will then meet with the Food and Drug Administration and work with them to then design subsequent clinical trials to look and to measure the activity, the efficacy, and the safety of this drug in bladder cancer patients.

Dr. John Taylor: The goal is to have that open here.

Dr. Shrikant A.: I was going to ask you, so at that point, our patients in KU, in the hospital here in the University of Kansas Cancer Center, they will have an opportunity to also participate if they're eligible for the trial.

Dr. Scott Weir: Yeah, and exactly, Shri and really that's the vision for our Cancer Center. The vision of our Cancer Center is To transform bedside and bench discoveries into promising new treatments for cancer, diagnostic tests for cancer, to be able to bring that research to our patients.

Dr. Shrikant A.: Yeah, thank you. As we approach the end of today's Bench to Bedside session. Dr. Taylor, Dr. Weir, any final takeaways?

Dr. Scott Weir: Well, I guess if I could just say the effort required to discover and develop a new treatment really requires a team.

Dr. Shrikant A.: A village.

Dr. Scott Weir: We like we like to say it takes a village and that's the approach we take here to discovering and developing new treatments. It not only takes a village of researchers within our university, but also partners in our region and certainly the private sector. What We've built here is an innovative approach to partnering with the private sector to be able to bring these promising treatments forward to patients.

Dr. Shrikant A.: When you say private sector, you're talking about research organizations in the private sector as well as investors and-

Dr. Scott Weir: Exactly.

Dr. Shrikant A.: ... everybody?

Dr. Scott Weir: All of all of above.

Dr. Shrikant A.: All of the above.

Dr. Scott Weir: That would include, again, working with the Food and Drug Administration to be able to bring these treatments to patients.

Dr. Shrikant A.: And John?

Dr. John Taylor: Yeah, I think that from a patient perspective and from a provider perspective, it's been very frustrating in the past 20 plus years of practice that we haven't had something new for patients. 10 years ago, the field of novel drugs or treatments for bladder cancer was an arid desert. For my patients and all those who were afflicted with this disease and their care providers as well, it's a very exciting time because we're finally beginning to see a wave of novel agents on the horizon. I think that we here at KU are very well situated in the middle of that wave. It's a very exciting time, they can't come fast enough. For our patients, these novel agents cannot come fast enough, and I think that we're on the verge of seeing a whole host of them explode.

Dr. Shrikant A.: One final point I was wondering, we are talking about therapy, but this could also potentially be a preventive. Once we've given them as a therapeutic, we might potentially be able to move it to like an aspirin. This could potentially be a therapeutic or a prevention agent so that the patients may not have a record, which is the biggest problem right now.

Dr. John Taylor: That's one of the biggest issues with bladder cancer. It's not only treating the initial tumor, but patients are at risk of recurrence for the rest of our lives. We need something that can handle the current disease as it presents and then reduce their risks of recurrence, and by doing so, reduce the risk of progression throughout the rest of their life.

Dr. Shrikant A.: Alicia, she's here in the studio at taking questions. Any final questions, Alicia?

Alicia Miller: There are no more questions at this time, but if you have any more questions or comments, please submit them and we will monitor throughout the day.

Dr. Shrikant A.: Thank you Dr. Taylor, Dr. Weir. This has been for being here today with us and telling us about the latest and greatest of the University of Kansas Cancer Center in relation to bladder cancer. Please, do visit the kucancercenter.org website. We appreciate all of you joining us. Please let your friends know, your colleagues know, your family know, they can go into our Facebook site and they can find this video. It will be up there. Thanks for watching.

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