***This blog is the first in a three-part series on bladder cancer.

For too long, bladder cancer has been called the invisible cancer. But a recent convergence of strong philanthropic support and promising research findings are improving awareness and treatment of bladder cancer.

Despite being the fifth most common cancer in the United States and claiming the lives of approximately 16,000 people nationwide annually, bladder cancer is sometimes referred to as the invisible cancer. Compared to some other cancers, bladder cancer doesn’t receive a lot of attention in the media and gets significantly fewer research dollars. In 2013, for instance, the best-funded cancer received over $500 million by the National Cancer Institutes (NCI), the largest funder of cancer research in the United States. In comparison, bladder cancer received just $20.3 million from the NCI. “That is almost last among all cancer types, says Noah Hahn, M.D., medical oncologist and bladder cancer specialist at the Johns Hopkins Kimmel Cancer Center.

Noah Hahn

Noah Hahn, M.D.

As Hahn points out, bladder cancer is not invisible to the patients battling the disease or to those physicians who care for them. And fortunately, bolstered from a recent generous infusion of philanthropic support, Johns Hopkins physician-scientists are pursuing some exciting research avenues that may increase recognition of the disease and significantly enhance outcomes for those who suffer from it.

“As my career has moved forward, important pieces—both the research and key partnerships—kept coming together. I think that’s why today, we’re a lot more excited about our opportunities to change outcomes in bladder cancer than we ever have been,” Hahn says.

Philanthropy, Advocacy Network Support Bladder Cancer

A generous gift of $15 million from Erwin and Stephanie Greenberg in 2015, along with a $30 million co-investment from The Johns Hopkins University, established the Johns Hopkins Greenberg Bladder Cancer Institute. Its focus is on much-needed research dedicated to improve understanding of and treatment options for bladder cancer. The institute draws expertise from multidisciplinary professionals within Johns Hopkins and, eventually, throughout the world.

“It’s bringing together talented individuals from the Brady Urological Institute, radiation oncology, pathology, medical oncology, and bioinformatics to focus intensely on bladder cancer,” Hahn says.

Another important source of funding for bladder cancer, notes Hahn, is the Bladder Cancer Advocacy Network, a community of advocates, survivors, and medical and research professionals united in support of people affected by bladder cancer.

The network recently awarded a second bladder cancer innovation award and a series of grants over several years to young investigators. “Our hope is that when people see this type of philanthropic support to the Greenberg Bladder Cancer Institute, it will have a ripple effect. I have full confidence that we will also see other gifts made to other bladder cancer focused organizations,” Hahn says.

In addition to the need for philanthropy, Hahn also emphasizes the importance of developing industry-academic partnerships specifically to fund bladder cancer research, particularly projects related to immune therapies and targeted therapies—two emerging areas of research that offer great promise.

Promising Bladder Cancer Research Initiatives

Targeted Drug Agents

Much of the emerging cancer drug research involves identifying and targeting specific genetic mutations and pathways responsible for the development and spread of the disease. To date, no such targeted drug agents have been approved to fight bladder cancer. But some exciting recent developments are bringing researchers closer to this reality.

A breakthrough came in 2014, when The Cancer Genome Atlas Research Network created a detailed molecular profile of an aggressive invasive form of bladder cancer. The research uncovered important genes and pathways that are commonly disrupted in bladder cancer. It also enabled researchers to discover that some specific subtypes of bladder cancer exist, much like we have known for years in breast cancer and other cancers.

“It gave us a road map for how we should attack lethal bladder cancer, answering questions such as what are the different subsets of biology, how prevalent are they and what targets are present in enough of these patients to make clinical trials feasible in these molecularly defined bladder cancer subsets,” Hahn says. “I think we’re just at the tip of the iceberg in our understanding. We’ll be overjoyed to see the first trial completed that works. We want to get there yesterday. I think it will happen in next couple of years.”

Immune Therapy

Immune therapy is yet another promising area of research in the fight against bladder cancer.

Immunotherapy is not an entirely new approach to treating bladder cancer. In fact, in 1990, bladder cancer was among the first types of cancers in which immunotherapy was granted approval for therapeutic use by the Food and Drug Administration. Now, BCG therapy—immunotherapy with a weakened, live bacterium, bacillus Calmette-Guérin—is a routine part of treatment for many patients with early-stage bladder cancer. BCG therapy has reduced the risk of cancer recurrence and decreased the chance of cancer progression, as the majority of patients who receive it go into remission.

Now, Hahn and other researchers are exploring another form of immunotherapy in patients with bladder cancer through the use of checkpoint inhibitors. Anti-PD-1 and anti-PD-L1 drugs are promising checkpoint inhibitors that, in theory, act by taking the brakes off the immune system, allowing it to function normally so that it will eradicate the cancer.

Among patients getting checkpoint inhibitors via clinical trials are those with metastatic disease already treated with chemotherapy. The survival rates of this group are double those for patients with a similar disease profile who are not on the trial. “We’ve never seen that in second-line therapy before,” Hahn says. “It’s too early to say that we’re curing patients. But it is extremely encouraging that responders do seem to be doing well. We’ll feel even better if we’re three to four years out and seeing the same type of results.”

While he is careful not to refer to these checkpoint inhibitors as a potential cure, “they have created a lot of excitement in our patients who have been eagerly in need of innovations for a long time,” says Hahn.

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**This blog post was written by Kimmel Cancer Center development coordinator Allison Rich.

Ben Park, M.D., Ph.D., was recently named the Johns Hopkins Kimmel Cancer Center’s associate director for research training and education. Already an internationally recognized physician-scientist committed to training and mentoring young students and faculty members, Park’s new role allows him to even more actively shape a future that, once again, places education at the forefront of academic medical science. By designing and implementing solutions that will increase the appeal of the lengthy and arduous doctoral training tracks, Park plans to help ensure that today’s most brilliant minds continue to develop the treatments we need in the clinics of tomorrow.

As part of his charge to develop an overarching vision for how postdoctoral education should be approached at the Kimmel Cancer Center, Park has invested in finding a solution capable of securing the future of cancer research — a solution that he views with a sense of urgency.

Ben Park

Ben Park, M.D., Ph.D.

“We need to halt the current level of attrition in academic research training programs. That’s the only way we are going to cure cancer,” says Park. “Our work is predicated on this notion of translating the best science from the bench to the bedside. The truth is that there will be very little bench left if we don’t rethink how we train our clinician-scientists and incentivize more young minds to go into this field.”

His two-pronged approach reshapes education by enhancing the formality of the postdoctoral training process and broadening the scope of opportunities available to postdoctoral students after they have completed their training. It has vast potential to transform how we approach advanced education across the medical field and simultaneously strengthens the educational component of the Johns Hopkins tripartite mission to advance patient care, teaching and research. His global vision underscores the idea that education is the most empowering component of our efforts, both for our faculty members and those who will pursue related careers in other facets of oncology.

By encouraging postdoctoral students to participate in industry internships, for instance, we can craft a mutually beneficial situation for postdoctoral students to expand their expertise and the cancer medical industry to develop relationships with potential employees who are well-versed in cancer medicine and ready to apply that knowledge to numerous facets of the field. Preparing students for research-related careers provides the unparalleled opportunity to allow the best and brightest trainees to influence how cancer is viewed socially, in public policy, in industry, and through regulation — not solely from the laboratory or the clinic.

In the field of cancer medicine, education is a lifelong commitment — and it is not a commitment that applies only to those who go on to pursue a career at the laboratory bench. Instead, Park underscores the importance of broader public awareness of what cancer is and what it is going to take to cure it. Ensuring that individuals across all facets of cancer medicine — scientists in the lab, entities who shape public policy or the pharmaceutical regulators at the Food and Drug Administration — have a thorough understanding of how to best approach cancer research, treatment and prevention, we can cement a surer path toward a cure together.

More information on cancer research training at the Johns Hopkins Kimmel Cancer Center

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What keeps you up at night? This was the question posed by Kimmel Cancer Center director William Nelson, M.D., Ph.D., to six cancer experts who participated in a Cancer Conversations forum on Nov. 3, 2015. In parts one and two of this series, they predicted the future of cancer medicine and discussed how they collaborate with other scientists. The panelists were:

  • Kimmel Professor and Director of Radiation Oncology and Molecular Radiation Sciences Theodore DeWeese,
  • Kimmel Scholar and GI cancer pathologist Laura Wood,
  • Kimmel Scholar and cancer biology cell division scientist Andrew Holland,
  • Martin D. Abeloff Scholar in Cancer Prevention and Control and Deputy Chair in the Department of Epidemiology at the Johns Hopkins Bloomberg School of Public Health Elizabeth Platz,
  • Co-Director of Cancer Immunology Charles Drake, and
  • gene sequencing expert Vasan Yegnasubramanian.

Questions That Keep Cancer Experts Up At Night

Yegnasubramanian:  How can we fill unmet clinical needs? I think about better biomarkers to test for and distinguish aggressive cancers from non-aggressive cancers so that we intervene earlier against aggressive cancers. Despite out best efforts, cancers alter their physiology and evade therapies. We need increased options for patients with advanced cancers and to devise combination therapies to treat initial disease and avoid resistance.

DeWeese: How can we decrease overtreatment and the harm it causes to patients? My goal is the development of a radiation signature for each patient that tells us which patients will require more treatment and what patients could be successfully treated with lower doses.

Chuck Drake: We are seeing remarkable responses with immune therapies, particularly with an immune target called PD-1. I saw two patients from our very first anti-PD1 trial who are still alive. Unfortunately, there are many patients who are not. I want to understand why those patients are still alive and others are not. What was different about their cancers and their immune systems?

Platz:  I think about measuring exposure and classifying people with respect to their exposures so we really can figure out what is causing cancer on a population level. The things we know about—smoking, obesity and physical activity—only explain about 50 percent of cancers in the population. What about the other 50 percent? In addition, there is a need to figure out ways to translate what we’ve learned about prevention into behavior changes so that we reduce the risk of cancer on a population scale and create healthier survivorship.

Holland:  I think about the variation in singles cells of the same type. We look at cells and they seem identical, and at the genetic level, they may be.  But, at the expression level they vary dramatically, but yet they behave very much the same. How does this relate to treatment resistance?

Wood:  I want to find biomarkers that distinguish common low-risk precancerous lesions from uncommon high-risk precancers so that we can identify and treat high-risk precancers and not overtreat those at low risk. There are still many gene variants that we don’t understand. We need to figure out which ones matter—how genes interact and what mutations are important. I envision new model systems to test for the relevance of mutations to cancer versus alterations that are just along for the ride.

Watch the forum:

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In part one of this series, experts at the Johns Hopkins Kimmel Cancer Center discussed their predictions for the future of cancer medicine during a Cancer Conversations forum on Nov. 3, 2015. These experts also discussed how they collaborate with other scientists. On the panel were:

  • Kimmel Professor and Director of Radiation Oncology and Molecular Radiation SciencesTheodore DeWeese,
  • Kimmel Scholar and GI cancer pathologist Laura Wood,
  • Kimmel Scholar and cancer biology cell division scientist Andrew Holland,
  • Martin D. Abeloff Scholar in Cancer Prevention and Control and Deputy Chair in the Department of Epidemiology at the Johns Hopkins Bloomberg School of Public Health Elizabeth Platz,
  • Co-Director of Cancer Immunology Charles Drake, and
  • gene sequencing expert Vasan Yegnasubramanian.

Collaborations Informing Cancer Research and Medicine

Platz:  The amount of methylation of DNA is critical to whether a gene can produce a protein or not—whether that gene is active or inactive.  I am collaborating with Vasan to study methylation patterns in individuals. One unique study came about through a Kimmel Cancer Center partnership with Howard University. We have developed a repository for umbilical cord blood to explore differences in methylation patterns to see if it may help explain why African American men have much higher risk of prostate cancer than white men.  Could there be underlying molecular changes in methylation patterns that begin very early in life and set people up for cancer later in life?

Drake:  We have a depth of expertise here in epigenetics and I am collaborating with experts to better understand immune responses to cancer. Perhaps some immune responses are being blunted by epigenetic mechanisms and we could develop drugs to target this.

Wood: We need to become more specific about what the cells we analyze. Tumors are a mix of tumor cells, immune cells and other cells. I’d like to expand the understanding of cancer biology to get a good read on what is happening within a tumor so that we may identify precursers that will allow us to detect cancer earlier and even prevent it.

Holland:  Cancer research has been empowered by new instruments that allow us to peer inside the living cell and see things happening with exquisite detail. In the laboratory, we can use them to manipulate the genome, change the genetic content of these cells, to see how it changes the physiology of these cells.

DeWeese:  Why do cells of different types respond differently to radiation therapy when they have the same DNA? Cell biology, using a biomedical engineering perspective may shed light on the biomechanics of how these cells are organized and how this dictates how they respond to therapy. If we can understand how structure influences how cells respond, there are things we can do to manipulate this structure and ultimately response to treatment.

Cancer is an evolutionary process. If we explore the things that we know can wipe out a species—changes in temperature, pH, and oxygen content—can we adapt evolutionary biology into cancer therapies? Can we use new technologies, for example, to alter the temperature in the microenvironment and stress cancer cells into death?

Yegnasubramanian: Computer science and engineering is key.  What we have learned about cancer through gene sequencing is exceeding our ability to analyze it. Within a decade, we will need innovations to store and process our genomic data with computing technology. How do we address this challenge and continue to make advances as we simultaneously work toward innovations that address these challenges?

Watch the forum:

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On Nov. 3, 2015, a capacity crowd of more than 250 Johns Hopkins leaders, faculty, staff, students, donors, and other guests filled the Albert H. Owens Auditorium at the Johns Hopkins Kimmel Cancer Center to honor the philanthropy of Sidney Kimmel for advancing cancer discovery and care. Hundreds more watched via video streaming as Kimmel Cancer Center Director William Nelson led a thoughtful discussion of challenging topics in cancer medicine and research by a panel of cancer experts, including Kimmel Professor and Director of Radiation Oncology and Molecular Radiation Sciences Theodore DeWeese; Kimmel Scholars, GI cancer pathologist Laura Wood and cancer biology Panel of experts at the Johns Hopkins Kimmel Cancer Centercell division scientist Andrew Holland; the Martin D. Abeloff Scholar in Cancer Prevention and Control and Deputy Chair in the Department of Epidemiology at the Johns Hopkins Bloomberg School of Public Health Elizabeth Platz; Co-Director of Cancer Immunology Charles Drake; and gene sequencing expert Vasan Yegnasubramanian.

The experts shared their views on several topics. The following are their opinions on what the future holds for cancer medicine. In two upcoming blogs, we'll share how these scientists are collaborating with others and the questions that "keep them up at night."

The Future of Cancer Medicine

Laura Wood, cancer pathologist: I hope to improve our ability to use pathology to figure out what treatment will help each patient.  There will never be one cure for everyone but rather different cures for different patients. This is what we call precision medicine. We need to continue to use pathology to divide cancers into smaller and smaller subsets to help decipher who will respond best to what therapy.

Andrew Holland, cell division researcher: Cancer is disregulated cell growth. If we understand more about the molecular differences between how normal cells divide and cancer cells divide, we can develop therapies that target cancer cell division and leave normal cells untouched.

Elizabeth Platz, cancer epidemiologist:  I envision ways we can intervene in cancer, beyond treatment, to prevent poor outcomes. We need to identify subsets of people who are likely to benefit more from specific strategies.  As we understand the biology of cancer better, we may be able to figure out better ways of using prevention strategies for people who have cancer and those who do not. For example, smoking is linked to cancer among the general population, but it is also a risk factor for poor outcomes in patients who already have cancer.

Charles Drake, cancer immunologist: Some cancers are recognized by the immune system and immune therapy—using the immune system to fight the cancer—should be a first line therapy for these patients. Some patients have tumors that don’t readily respond to immune approaches, and for these patients we’ll need to develop combinations of radiation and conventional therapies along with immune therapies to have an impact.

Ted DeWeese, radiation oncology expert: We will expand our use of sophisticated data warehouses that have patient history, physical exam, imaging, laboratory studies, and genetic information embedded in them along with structured information on treatment outcomes and related side effects. We have built such a system in radiation oncology that analyzes any treatment plan and adjusts it to create an optimal plan that maximizes therapeutic benefits and minimizes side effects. It has already been deployed at the Kimmel Cancer Center and is now being expanded nationally, in Canada and Japan. The world of oncology changes when we have millions of patients to reflect upon to devise the best treatment for every individual patient.

Vasan Yegnasubramanian, gene sequencing expert:  Many of the problems we face today can be addressed through a convergence of technologies. Sequencing and the data it provides is revolutionizing how we make treatment decisions. There is an immense depth of information we can harness, but we need to figure out how best to gather it and how best to use it.

Watch the Conversations on Cancer forum: 

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The Johns Hopkins Kimmel Cancer Center joined all of the nation's cancer centers designated by the National Cancer Institute in endorsing human papillomavirus (HPV) vaccination to prevent cancers caused by the ubiquitous virus.

HPV infections are known to cause most cervical, anal, oropharyngeal and other genital cancers. Vaccines are available to prevent infections of certain strains of HPV and are recommended by the CDC for boys and girls at ages 11 or 12 years.

However, vaccination rates remain low in the U.S. The published statement reflects the Cancer Centers' message to parents, adolescents and health care providers about the importance of HPV vaccination.

NCI_HPV_Consensus_Statement_012716

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Yesterday's announcement from the United States Preventive Services Task Force of its final recommendations on breast cancer screenings was met with disagreement from many doctors who specialize in breast imaging. Dr. Susan Harvey, director of Breast Imaging at Johns Hopkins joined others who said the announcement will not change their own practices.

"What this controversy has brought to light is the urgent need for us to demonstrate how modern breast cancer screening is cost effective, scalable, saves lives and equally valuable to a woman in her 60s as well as her 40s, where breast cancer caught early has a lasting impact in costs to society and our workforce," says Harvey.

Read more information from Johns Hopkins experts discussing breast cancer screening:

  • Breast cancer screening controversy: expert Susan Harvey authored this op-ed in April with her take on the topic.
  • Breast Imaging director Susan Harvey discusses mammography and tomosynthesis in this video.
  • Watch a video on "What you need to know about Screening Mammography."

 

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***This post was written by the Kimmel Cancer Center's Chief Administrative Officer, Terry Langbaum, in memory of Ellen Stovall, late president of the National Coalition for Cancer Survivorship, who died Jan. 5.  

The first time I met Ellen Stovall, we immediately felt that we had known each other for years. We had so much in common -- our mutually shared medical histories, yes, but much more importantly, our mutual determination to make life better for cancer patients and cancer survivors. Ellen used all of her resources to make a difference in the lives of cancer survivors, and did she ever have resources. She was intelligent, determined, articulate, endlessly energetic, genuine, and intuitive. She was comfortable with medical professionals of the highest order, political leaders at the national level, cancer advocacy professionals, patients and caregivers. In the National Coalition for Cancer Survivorship, she was able to create and build an advocacy organization that filled a gap by recognizing and giving voice to so many individuals experiencing the late effects of cancer treatment, including chronic pain, chronic anxiety, some pretty awful co-morbidities caused by cancer treatment, and the very real risks for secondary cancers in those who have had cancer treatment. Until her last day, Ellen continued to do what she passionately loved. I hope I am that fortunate. Today, cancer researchers work tirelessly to find treatment protocols that cure the cancer, but that reduce the late health risks associated with cancer treatment. In no small part, this is a result of Ellen Stovall's life's work. We can all honor her memory by continuing her legacy.

Terry S. Langbaum
Chief Administrative Officer
Kimmel Cancer Center at Johns Hopkins

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The following response was provided by Drs. Cristian Tomasetti and Bert Vogelstein in regards to a new paper published in the journal Nature:

Scientific debate on the factors responsible for cancer is a welcome and important part of solving the challenges we face in reducing the burden of this disease . The differences between our conclusions and those of Hannun et al. are dramatic. Through re-evaluation of our data, the authors conclude that virtually all forms of cancer are the result of extrinsic factors (Fig. 3 of Hannun et al.). Their analysis therefore supports the widely held belief that nearly all cancers of all types are preventable.

In contrast, we concluded that some cancers are largely the result of environmental factors — such as those associated with exposure to cigarette smoke or sunlight, or obesity — while other cancer types are largely unavoidable. Moreover, we concluded that all cancers, of all types, are likely to be caused by a mixture of the mutations induced by external influences — avoidable in principle — and those caused by the replication of normal stem cells — unavoidable and just bad luck. Our conclusions were based on our discovery of the extraordinarily tight relationship between stem cell divisions in normal tissue and the incidence of cancer in that tissue. The striking contrast between our conclusions and those of Hannun et al. has important implications about the information that should be provided to cancer patients and the public.

We were surprised that Hannun et al. attempted to determine the proportion of individual cancers due to extrinsic factors from our stem cell data, because that is impossible to do in a reliable and mathematically sound fashion. This explains why some of the authors’ estimates of the contributions of extrinsic factors to cancer are incongruent with the voluminous epidemiologic research on these cancers. For example, Hannun et al. concluded that more than 99 percent of prostate cancers, more than 98 percent of thyroid cancers, more than 95 percent of brain cancers and more than 94 percent of testicular cancers are caused by environment factors (Fig. 3 of Hannun et al.), while epidemiologists have concluded that zero or less than 1 percent of any of these cancer types can be ascribed to extrinsic factors (http://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type).

In contrast, we believe that the estimates made by decades of painstaking work by epidemiologists are accurate, i.e., that between 21 to 42 percent of cancers in the U.S. are preventable. We attempted to identify the risk factors that might have contributed to the remaining cancers. We discovered strong evidence supporting the idea that replicative mutations, made during normal stem cell divisions, are a major risk factor. Our analyses further indicated that certain cancers, such as those of the lung and skin, had a much larger non-replicative component than other cancers, such as those of the brain, bone or pancreas.

Our study was the first to provide scientific evidence to support the idea that we can now confidently tell most parents of children with cancers, as well as adult patients with certain types of cancer, that there was nothing they could have done to avoid their plight. By perpetuating the myth that virtually all cancers are due to extrinsic factors, we can inadvertently add guilt to already tragic situations. At the same time, our study confirmed the well-known importance of avoiding the known risk factors for cancer, such as cigarette smoke, sunlight and obesity.

Cristian Tomasetti
Bert Vogelstein

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In today’s news, former President Jimmy Carter, who has metastatic melanoma, revealed that he has responded well to treatment. We asked melanoma expert Evan J. Lipson, M.D., for his thoughts:

“I was pleased to hear President Carter’s report that his most recent MRI brain scan did not reveal any signs of the original cancer spots nor any new ones. While we don’t know whether President Carter is completely free of melanoma, it’s encouraging to see a 91-year-old man tolerating his treatments well and continuing to work at his foundation.

“My understanding is that the president has been treated with surgery, radiation therapy and a drug called pembrolizumab (anti-PD-1). Pembrolizumab is a relatively new medication that activates the body’s immune system to fight melanoma. In some patients, when the immune system is activated using pembrolizumab or another similar medication, nivolumab, it can attack the cancer and bring about a remission that can last for months or sometimes years. These medications have also demonstrated efficacy in some tumor types other than melanoma.

“I hope that positive outcomes like this one will be encouraging for other patients battling cancer.”

More information about melanoma and immunotherapy is available from the Johns Hopkins Melanoma Program. Look for the next issue of Promise & Progress, which will feature immunotherapy

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