University Place

>> I'm so delighted that you're joining us here tonight. This is a very, very wonderful and special week. Spring has sprung, and, best of all, we have a true dream team here tonight for another episode of our Mini Medical School. Now, I was going to say a few words about Mini Medical School, but as I look around, I see so many familiar faces. Just out of curiosity, by a show of your hands, how many are here for a repeat attendance? Wow. That's great. How many are here for the first time? Ah. Well, this program just continues to grow, both in the popularity, and the repeat attendees are really quite impressive, but also in terms of its capacity to really demonstrate the amazing scope of all the activities that go on here in the School of Medicine and Public Health cuts across all the major categories of health and disease, and in each presentation, including tonight, it demonstrates the incredible power of bringing together basic science, clinical science, population health science, and all the translational activities that bring them all together in a single package. And tonight's dream team will be a wonderful repeat demonstration of how that UW model works so well. So without further ado, I want to introduce again the remarkable deans of our Mini Medical School. The chair of our Department of Medicine, Rick Page, and the chair of our Department of Surgery, Craig Kent, and they're going to get on with the show. So, welcome and On Wisconsin.

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>> Well, thank you, Bob. And thank everyone for coming and attending tonight. It really is, I think, gratifying to both Rick and I to see so many people coming back for more. And I hope this means that you're enjoying Mini Medical School, you're learning from this, and we certainly, from both of our standpoints, very much enjoy being you're mini deans. We try to pick a topic each time that is of interest to everyone, and the topic we've chosen today, which is cancer, is a serious topic. If you look around the country, each year 1.6 million people are diagnosed with cancer. About 600,000 die of cancer each year. For many years it was cardiovascular disease that was the number one killer in this country and it still is, but it's almost to be eclipsed by cancer. So this is a serious problem, and my guess is there's no one in this room who hasn't been affected through a loved one in one form or another through cancer. So it's a problem, but it's one that I think here at UW we're really tackling in a major way. We have some incredibly innovative cancer physicians here, both clinical and in research, and we want you to spend some time with them tonight. If you look at our-- we actually have what's called a National Cancer Institute designated cancer center. And if you look around the country, there are 41 of those institutions in the country, and one of those is here in Madison at UW. In fact, the only one in the state. So we have the expertise, we have the innovation, and we're really going to take pride tonight to be able to show you some of the really great things we're doing at UW around trying to cure this very, very difficult disease. >> Well, thanks, Craig. And from my standpoint, I also appreciate Bob's support in this kind of being an idea that Craig and I had five years ago now, and, really, it's grown wonderfully. Before we get started, though, I think it's important for us to introduce the real experts and our leaders through tonight's event. And those are the names you see on the screen here. Howard Bailey, who's professor of medicine in my department as well as an OB/GYN and is newly named the director of the University of Wisconsin Carbone Cancer Center. He is partnering with Paul Lambert, who is the Howard Temin Professor, and that name will mean more to you later on this evening, and chair of oncology and director of the McArdle Laboratory for Cancer Research. Both of them have ties. Dr. Lambert took his PhD here at the University of Wisconsin, and Dr. Bailey is a graduate of our training program in hematology oncology. So they're Wisconsin through and through, and they're going to take us through the journey this evening as we learn about the multidisciplinary approach to cancer. But before we get started, I want to present to you just a clip from the emperor of all maladies. No one has gotten to see this before us. I actually got to see it today just on my computer screen, and it's going to be an outstanding program. And we'll start with this clip, and then we'll go directly to Dr. Bailey and Dr. Lambert taking over the microphones and taking us through our journey this evening. So, please enjoy this little snippet of the upcoming documentary. >> Cancer is not one disease; it's many. But each of them begins in the same way, with the uncontrolled growth of a single cell. It attacks the blood, the breasts, the lungs, and every other part of the body. No one is immune to cancer. Not young nor old, rich nor poor, frail nor strong. >> Cancer wants to live at the expense of your entire body and your entire being. It doesn't care about you. It doesn't care if you're a mother or a husband or a daughter or if you have four children. It doesn't care. It just cares about itself. >> This is a struggle of life and death, and we cannot win if we're afraid. >> But human beings have refused to surrender. Have always struggled to understand it. Was it God's curse? Could you cut it out? Could you burn it? Could you poison it? Was it a virus? Did it come from the outside? Or did the enemy lie within us? In the ongoing struggle to conquer cancer, massive force has sometimes meant defeat. >> So this will be your last cycle. >> Tragic failure has lead to remarkable success. And final victory always seems just out of reach. The struggle has reflected every human's strength and frailty, resilience and terror, candor and denial, arrogance and caring. >> You're doing good. >> Blind allegiance and leaps of faith, hubris and hype, and genuine hope. Cancer has been called many things. The king of terrors, a hidden assassin, and the emperor of all maladies. >> Cancer has taken on this larger than life role in our culture and our lives. It is the word that we relate to with simultaneous terror and some humility. It makes us resistance workers. It makes us historians of that empire. It makes us people who grieve about what happens when this invades our lives. It makes us soldiers. But every year has brought a kind of clarity to our understanding of what goes wrong in a cancer cell and what can be targeted, can be prevented, can be treated. >> Every field in medicine has had a moment in history that has been transforming. The moment where the knowledge that was acquired to change the field became available.

CHEERS

And my prediction is that the next 20 years is going to be the age of discovery for cancer and the age for new therapies. This is our time.

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>> My name is Howard Bailey and this is my colleague Paul Lambert, and, again, welcome everyone. And we want to thank Dr. Golden, Dr. Page, Dr. Kent for the opportunity here tonight. The clip that was just shown on the upcoming documentary by Ken

Burns on Cancer

The Emperor of All Maladies really details the enormity and complexity of cancer. The book and the documentary are going to go into and describe the cancer research history and, if you will, the cancer research future that is before us. The University of Wisconsin has been a great contributor to that cancer research history, and we are going to show you tonight both that history and that cancer research future that the University of Wisconsin's been greatly involved in. The history at the University of Wisconsin in cancer research really starts with Harold Rush, a native of the Wausau area, who founded both the McArdle Laboratory for Cancer Research and the University of Wisconsin Comprehensive Cancer Center, now called the Carbone Cancer Center. >> Thank you, Howard. So, indeed, this year we are celebrating 75 years of cancer research here in Madison. And, as Howard mentioned, there is a rich history of seminal discoveries that have been made here in Madison that transform both our understanding of how cancer arises and how best to treat cancer. Tonight, we're going to hear four stories that bridge critical discoveries made here in Madison with the state of the art new approaches to treating cancer. I'm sure you're going to recognize the passion that researchers and clinicians here in Madison bring to their efforts to understand and to better treat cancer, the emperor of all maladies. I'm privileged now to introduce the first speaker, Professor Paul Ahlquist. Dr. Ahlquist is a distinguished member of the McArdle Lab for Cancer Research, a member of the National Academy of Sciences, and investigator at the Howard Hughes Medical Institute. Dr. Ahlquist studies the role of viruses in human cancer. Tonight, Dr. Ahlquist will provide the first vignettes leading us from the historic discoveries by Dr. Howard Temin made in McArdle regarding retroviruses to new discoveries being made today that could lead to better treatment of cancers caused by viruses. So, Paul.

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Burns on Cancer

>> Thank you. As was indicated, I'm going to talk to you today about tumor viruses, the cancer they cause, and approaches to control both the viruses and those cancers. And in the course of that, I'll talk to you about some of the foundational work in this area in Madison by Howard Temin and work continuing then to the present day. Now, as background for this, I should tell you that it's now well established that viruses cause at least 15% of human cancers. And in most of these cases, the viruses not only initiate the process of tumor development but also in the final mature cancer contribute viral genes that are essential for the continuing survival of the tumor cells. So the implication is that inhibiting virus infection or the right viral functions could potentially prevent or cure many cancers. Now, today then, as an introduction to these topics, I'm going to tell you about Howard Temin's Nobel Prize winning discovery of retroviral reverse transcriptase. I'm going to outline for you in brief the current broad, vigorous efforts in Madison on tumor virus research, and, in the course of that, particularly highlight two selected translational projects that have a significant potential to control tumor virus associated cancers. So Howard Temin was a professor at the McArdle Laboratory for Cancer Research, and at the time he was pursuing the research I'm going to discuss, which is the mid to late '60s, the field was dominated by a concept called the central dogma of molecular biology, which held that information flowed unidirectionally in this downward direction from DNA genes through an intermediate or messenger molecule called RNA which, in turn, directed the synthesis of a protein gene product that carried out the function of the gene. Temin was studying what were then called RNA tumor viruses. These were viruses that were known to cause cancers in animals and subsequently would be shown to do so in humans. And it was well established that these viruses carried their genes and their infectious particles and delivered them to cells in the form of RNA, this intermediate molecule. But in Temin's research, he found increasing evidence that later in the infection the viral genes were found in a DNA form. This was a shocking, radical concept for the time and was met widely with ridicule and scorn because this violated the central dogma. Temin was suggesting that contrary to this downward allowed information flow, RNA could direct the synthesis of DNA. This was explicitly forbidden in this world view. And so, again, although he developed increasingly strong evidence for the existence of this DNA stage, he was continually met with skepticism and denial. Well, finally, in 1970, he crushed this opposition and revised this central dogma by isolating the enzyme that carried out this process and carrying out this conversion of RNA into DNA in the test tube. And so this, since it's a normal process of DNA to RNA synthesis was called transcription, this new step came to be called reverse transcription, and the RNA tumor viruses were then

renamed for this backwards step

retroviruses or backward viruses. So Temin's finding that RNA tumor viruses operated by converting their RNA contrary to the then held concepts into DNA, this finding was immediately recognized as a game changing development in biology. And so he was quickly then rewarded with the Nobel Prize for this work. And among many other impacts of this work, this provided an explanation for how an RNA tumor virus could produce a heritable stable change in cellular DNA, and it was a critical step in the growing conceptualization that cancer always results from changes in the cellular DNA. His work also directed a new renaissance of effort in RNA tumor viruses, and that led, then, very quickly to the discovery of what were called oncogenes, named after the Greek word for cancer. These were specific genes that cause cancer often by deregulating cell growth, and these oncogenes now then are central to our modern concepts of what cancer is and how it can be treated. Temin's work also generated critical foundations for understanding and controlling

another retrovirus

HIV, which, of course, is clearly now the most devastating modern virus. Since the HIV epidemic emerged, at least 40 million people have died and at least 35 million are now infected. Temin's work with reverse transcriptase laid the foundation for reverse transcriptase inhibitors, which became the first anti-HIV drugs and now, with other drugs in continuing combinatorial therapy, are saving millions of lives. Finally, Temin's work also revolutionized our concepts of molecular biology by changing our thinking about evolution and also by providing critical tools that are now used for studying all genes. Temin's legacy in this work lives on very strongly at UW Madison in a very vigorous community of virus researchers, and particularly in the Carbone Cancer Center in its human cancer virology program, which is very actively and directly defining the mechanisms by which these tumor viruses replicate and cause cancer and developing approaches to prevent these infections and to either prevent or treat the associated cancers. Now, to accomplish these goals, this program has 12 UW faculty across a range of departments and schools, and they study six tumor viruses which collectively cause a great many important human cancers. Now, out of all of the diverse work in this program across these viruses and out of all the many advances, I want to outline briefly for you today then two selected examples of projects with Epstein-Barr virus and human papillomavirus that have significant potential then to prevent or treat these cancers. Now, first I want to talk about activating the Epstein-Barr tumor virus to selectively kill EBV, Epstein-Barr virus, positive tumor cells. So EBV is a DNA tumor virus that causes multiple important cancers, including Hodgkin's and other lymphomas and gastric and other carcinomas, and in all of these tumors, then the virus, Epstein-Barr virus, is present in each tumor cell. And our colleague Bill Sugden has shown that this is because the virus provides functions that are essential for these tumor cells to continue to survive in the body. Shannon Kenney has built on these foundations by taking the fact that in the tumor cells, EBV naturally exists in a restrained latent state in which it expresses relatively few genes that then promote tumor development and the survival of tumor cells, but she and others have shown that EBV can be awakened from this latent state into a state of active replication which, among other characteristics, kills the cells in which it's replicating. So since the virus is selectively present in the tumor cells, then this selectively kills the tumor cells while leaving the healthy cells alive. And accordingly, Shannon is working to increase the efficiency by which this cell killing can occur as well as on other approaches to control these EBV associated cancers. Now, in my second example I want to talk about controlling human papillomavirus induced cervical cancers through estrogen receptor inhibitors. So papillomaviruses have been estimated to cause 5% or more of all human cancers. This includes, for example, head and neck cancers in men and, as most people appreciate, essentially all cervical cancers in women. Cervical cancers being a very important cancer worldwide. It's the leading cause still of cancer death for women in many developing countries. Now, clinical data, longstanding clinical data, and results from Paul Lambert's mouse model studies show that in addition to contributions from two papillomavirus oncogenes called E6 and E7, the development of cervical cancers and the maintenance of these cancers in the bodies require continuing estrogen stimulation through the major estrogen receptor alpha. And Paul's further work in mouse models show that estrogen receptor inhibitors can block cervical cancer development by blocking this signaling and can also, if they're applied late after cancer has arisen, they can cause dramatic regression of these tumors. So, just as with the selective EBV directed killing of tumor cells, this looks very promising as an approach to control these cancers, and so Paul Lambert and also Howard Bailey are working to develop clinical trials now to test in high risk patients for the ability of these approaches to protect either against cervical cancer development or its recurrence. So, in summary, the take-home lessons from this first mini course in your Mini Medical School are that viruses cause at least 15% of human cancers and that Howard Temin's discovery of reverse transcription dramatically advanced our understanding and our abilities to work on virus and cancer research and treatment and that across a wide range of labs and viruses, ongoing work at UW is advancing our understanding of these tumors, their cancers, and the control of both. Thank you.

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another retrovirus

>> Thank you, Dr. Ahlquist. So the next clinical vignette and kind of branching and bridging history you're going to hear about is from Dr. Paul Sondel. Dr. Sondel is the Reed and Kara Lee Walker professor of childhood cancer research, is the head of the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant, and professor of the Department of Pediatrics, Human Oncology, and Genetics. Again, Dr. Sondel will be talking about the mobilizing the immune system to cure cancer from bone marrow transplantation to cellular immunotherapy at the University of Wisconsin Carbone Cancer Center.

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another retrovirus

>> Thank you very much, Howard, and thanks to all of you for being here not only to learn, but to show your support for UW and the really incredible work that's being done here. It's a real privilege to be able to come to work here every day and work with the kind of colleagues you're meeting tonight who are representative of the faculty at all levels here in our School of Medicine and Public Health. So I'd like to talk tonight about how lab results are being translated to help patients with cancer. And we've made a lot of progress in treating cancer. Treating cancer in children, our cure rates are on the order of 80%. Our cure rates in treating adults with cancer aren't that high, but we still made much, much progress. But yet, when everybody hears the word cancer, your heart stops for a second. We'd like to convert cancer into a disease that when people hear the word, they think now about the way we think about pneumonia, which used to be uniformly fatal a few generations ago. So, why in 2015 are patients still dying of cancer? Using the modern therapies that we have available, surgery, radiation therapy, chemotherapy, the mainstays of treatment, we can take almost any patient with cancer and put them into a state of remission. This means we can get rid of 99.9% of their cancer so that we can't even see it anymore by any standard clinical test. The trouble is after getting rid of 99.9% of the cancer, you're still left with a billion cancer cells. They're just too small to see. And if any of those cancer cells are still surviving, they will start to grow and relapse, and the cells that relapse are resistant to those standard therapies. So the approach I'd like to talk about tonight involves recent progress in an area called immunotherapy. The use of the immune system, that same immune system that protects you from viruses like the flu or from bacteria or that same immune system that could reject a kidney transplant if you need one. If the immune system could reject a whole kidney, hopefully we could turn it against cancer. And there's been so much progress in this field in the last few years that two years ago the journal Science announced its breakthrough of the year, which it does every December, and it picks any scientific field, it could be chemistry, it could be enzymology, it could be looking at astronomy, and two years ago, Science decided that cancer immunotherapy was the number one breakthrough for 2013, and it's because of some of the research that you're going to be hearing about tonight. Now, how does the immune system work? The immune system protects us, as I said. It can attack our normal tissue in the form of autoimmune disease like lupus or rheumatoid arthritis. But the immune system starts in the bone marrow, and it grows into a variety of different cells that look different and doctors can look at these cells and identify how they work and now we're able to use them in a way that proactively helps us fight cancer as well as many other diseases. The story of the immunotherapy for cancer, where we're trying to use the immune system to attack cancer really begins here, again at the University of Wisconsin. And it begins with the world's first bone marrow transplants done by Fritz Bach, who I'm very proud to say was my mentor. Fritz Bach came to the University of Wisconsin in 1965 following training at Harvard and at NYU. And he was a investigator who studied the way white blood cells activate one another, and he studied how they could do this in the test tube, in vitro. And he was very interested in understanding why kidney transplants get rejected. So he invented a test, a test that he called the mixed leukocyte culture test. And this is actually one of his slides from back in 1970 that I used for 10 years as a Kodachrome slide and them converted it to this PowerPoint presentation. So that's why it looks faded.

LAUGHTER

another retrovirus

But I show it for historical reasons because Fritz had the genius of setting up in the test tube what would be happening in a patient as far as a transplant. So he was studying a whole transplant in a test tube, and he could study how a transplant could be rejected but in the setting of a bone marrow transplant, he could study an

even more important reaction

how the immune cells from the healthy donor, when they get into the patient who needs the transplant, could attack every tissue in that patient, a reaction called graft-versus-host disease. So using this test in 1968, Fritz was able to identify a boy who needed a bone marrow transplant for immune deficiency disease and pick which of his siblings was a perfect match for transplantation to minimize graft-versus-host disease. He did that transplant in summer of 1968 and it was effective and that work, as I pointed out, was published in December of 1968 and I had the privilege of joining his laboratory as a sophomore undergraduate student here at the university in 1969. I stayed on with his laboratory and took time off from medical school to come back to his lab and do a PhD. And, really, all of the laboratory research and the translational research that I've been involved with since that time, as well as so many of his mentees, really was based on the ideas and concepts that we used to talk about when we were working with him in the laboratory. So from that humble beginning of the first bone marrow transplant ever done here at the University of Wisconsin in 1968, in 2012 the worldwide bone marrow transplant community was able to announce that a million bone marrow transplants have now been done worldwide, and most of these have been done to treat cancer. And the question is, how does a bone marrow transplant actually treat cancer? We'll get to that. First, what is a bone marrow transplant? It's not something we do in the operating room to the patient who needs the transplant. We collect the bone marrow stem cells either by collecting them from the donor using a needle that goes into the large bones or by collecting them from the donor we can get them out of the blood. These are put into a bag and given IV to the patient who needs them. It looks like a blood transfusion, but the cells in there aren't just what you see in the blood. They're the cells that can form the blood forming factory, the bone marrow. This is a picture of a young girl, 12 years old, that we did a bone marrow transplant on back in 1984. I was her doctor. This is a picture 12 days after the bone marrow transplant. It takes about three weeks for the bone marrow stem cells that we give to the patient to start growing and form a normal bone marrow to be able to start healing all of the tissue injury that's associated with what we need to do to help get the bone marrow to grow. Clearly, this child is miserable at this time. This child is getting intravenous nutrition, she's getting intravenous blood products, she's getting intravenous antibiotics because she doesn't have an immune system and she doesn't have cells to fight infection and she doesn't have cells to repair injury. Fortunately, the bone marrow from her matched sister grew well in her. Two weeks after this picture, she started feeling quite a bit better. She could be discharged. And several months later, she gave me this picture. >> Wow. >> So this is back in the mid '80s. When she gave me this picture, she asked me to promise that, she'd give me this picture if I'd promise that any time I showed this picture I tell who's ever looking at it that that's really her own hair. Of all the things she had been through, that was the most important thing to her at that time.

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even more important reaction

She's now an elementary school teacher in the Milwaukee area in her late 30s and doing very well. Bone marrow transplants work well, not quite this well all the time, but most of the time. So, thank you, Fritz Bach. But how does the transplant actually cure the leukemia? So 22 years after that first bone marrow transplant, I had a chance to be working with the International Bone Marrow Transplant Registry. We analyzed data from over 2100 transplants done worldwide and looked at which patients had their leukemia come back and which patients had their leukemia go away for good. This complex graph that we published in essence showed that those patients that had some immune reaction going on after the transplant, some graft-versus-host disease, but not too much, had the leukemia stay in remission. While those patients whose immune systems were not being activated, were not being cured of the leukemia. The bottom line here is the way the bone marrow transplant cures the leukemia is because of the immune cells in the bone marrow transplant that attack the cancer. I know many of you have been here to Mini Med before. A year ago, I had the privilege of presenting at the Mini Med School on cancer immunotherapy, and in that presentation, I really focused on the way that antibodies are being used to make a real impact in treating adults and children with cancer. Tonight, I want to focus on how the cells of the immune system are having an impact, and that's what was shown by this work. So the whole goal is to take the immune cells that are either in a healthy individual and can attack the patient's cancer or to take the patient's own immune cells and get them redirected against their cancer so that they can destroy the cancer and get rid of it. And I'd like to highlight some of the really groundbreaking work that's being done here at the University of Wisconsin in this area. So Ken De Santes is the leader of our pediatric bone marrow transplant program, who believes strongly in this immunotherapy. He's taking the bone marrow stem cells from the donor and giving them to the patient. Just the stem cells. He's getting rid of all the other components of the bone marrow. But then in order to get this immune effect, he's devised a way to purify a population of immune cells called natural killer cells that are good at killing cancers but don't cause GVH, and he's giving them back to the patients. This protocol's been up and running for the past four years, and he's seeing very good results with it. We're excited about it. We're so excited that we're taking this one step further. Our colleague Mario Otto, while he was a fellow working at St. Jude, came up with a way to make this even more effective. What this slide shows, all these different colored cells are the different kinds of cells in the bone marrow. The cells that cause graft-versus-host disease, they're called alpha-beta T cells. They're the ones that are colored blue. Dr. Otto has devised a way to label those cells with an antibody that has magnetic beads stuck to them. You take this mixture of bone marrow that has the bad cells coated with magnetic beads and all the good cells aren't. Our put it through a column with a huge magnet on it, and the bad cells stay up in the column and the good cells go through and you transplant those. So Dr. Otto showed that this works in a test tube; it works in mice. His mentor moved back to Germany and has been doing this approach in Germany with great success. And this winter, Dr. Otto sent this approach to the USFDA, and we learned this winter that University of Wisconsin Pediatric Bone Marrow Transplant Program will be the first center in the United States to be doing this approach and it's been approved. Next innovation, the leader of our bone marrow transplant stem cell processing laboratory, Dr. Peiman Hematti, has been working with Christian Capitini to look at a different kind of cell you can find in the bone marrow, a cell called a MSC. They're able to take these cells and use these to help train a separate immune cell. All of this is done in vitro, in a test tube. But you then take these trained macrophages and these cells are able to stop graft-versus-host disease while it's starting. And what this slide shows is if mice are given a bone marrow transplant and they get these trained macrophages, you stop the GVH from occurring. So this is an approach that Drs. Capitini and Hematti are working to try and move into the clinical setting. Next, Dr. Capitini is really interested in regulating this graft-versus-host reaction to stop it but to try and get the graft-versus-tumor reaction to be maximized. And he's got a drug that's working in mice. And what this mouse experiment shows is if he gives mice cancer and then does a standard bone marrow transplant with them, these mice all still die of the cancer. But if he gives these mice immunotherapy where he vaccinates them as they're getting the transplant to turn on the right kind of an immune reaction, these animals now are resisting the cancer but they're dying of graft-versus-host disease. When Dr. Capitini treats them with this drug that can block graft-versus-host disease but not block the graft-versus-tumor effect, now these mice are surviving without graft-versus-host disease and without cancer. We want to move that into patients. So based on the depth and strength of cancer immunotherapy research being done here at our UWCCC, in 2013 we competed for what we think is not only a terrific honor but an incredible opportunity. Katie Couric, who you all know as a celebrity, news anchor, because of the death of her husband of colon cancer, started an organization almost a decade ago called Stand Up to Cancer where people in New York and Hollywood, largely media celebrities, have raised hundreds of millions of dollars in order to let cancer research move forward in a different way. To enable teams of investigators at different institutions to collaborate in a way that standard NIH grants really don't support. So with her support, this organization created a dream team for prostate cancer and for melanoma and colon cancer and breast cancer. And in 2013, they announced that there was going to be a dream team for childhood cancer research. So UW, along with a hundred other institutions, all put in our proposal for how we wanted to become a dream team. And we, along with these six other institutions, the National Cancer Institute, the Child's Hospital in Philadelphia, Baylor in Texas, Seattle, Vancouver, and Toronto, we were picked as the Stand Up to Cancer pediatric dream team. The focus of our work that allows to get the work from these seven institutions working together is to use the immune system and to use cancer genetics to identify new ways to treat cancer that no one of these institutions could really do by itself. So we're really pleased with the opportunity to collaborate with these other centers, and it's a privilege for me to lead our team of UW dream team investigators. These people, some of whose work I've talked about tonight, some of whose work I talked about a year ago at this same Mini Med School. I want to give one example. This is an example of a collaborative project that actually began at the Child's Hospital of Philadelphia. It was supported and it is supported now, this collaboration by Stand Up to Cancer. This is an approach that's gotten a whole lot of media attention. Incorrectly, the media has said doctors are curing leukemia with AIDS. That's not what's going on here. What is going on here is taking the legacy of Howard Temin's groundbreaking research in virology and using it to make a difference. So, white blood cells are taken from the patient with cancer. They're put into the laboratory in a test tube, a large test tube. A virus related to the viruses that Howard Temin was studying is then given to these immune cells, and it carries with them the genetic instructions that tell this immune cell how to specifically recognize and destroy the cancer. These cells are grown up to many hundreds of millions in the test tube and then given back to the patient with incredible results. None of this could have happened without Howard Temin's groundbreaking work. This study is now open at the University of Wisconsin. We just this month learned that it's approved, and my colleague Christian Capitini is our UW leader. In order to move this forward through this Stand Up to Cancer collaboration, the leader of this program at the Children's Hospital of Philadelphia, Dr. Steve Grupp, who's treated nearly a hundred patients with this approach and has phenomenal results, came here to Madison and spent yesterday and today meeting with our teams, helping us to get this trial up and running, and giving both pediatrics and the cancer center grand rounds. He flew back this morning, and after I said goodbye to him, I went to my computer and learned that he's actually featured in the clip you're going to see at the end of the program tonight in the Emperor of All Maladies clip because of this groundbreaking work that he's led and that we're doing as part of our dream team. So, in summary, we think there's a terrific future for the use of immunotherapy in the treatment of cancer. What we're doing at UW and what we want to move forward with is to expand the use of bone marrow transplant, and particularly cellular immunotherapy, because we're quite convinced that over the next decade this is going to be playing a role in the treatment of virtually every high risk cancer. But not only that, we know these approaches are going to be applied to a variety of other diseases, diseases different than cancer, like sickle cell disease, and severe autoimmune diseases, like rheumatoid arthritis, and a variety of other very severe medical problems. So our goals, with leadership from our dream team, with leadership from our cancer center and our faculty and both our adult bone marrow transplant clinical director Walt Longo and Ken De Santes from our pediatric team, is to provide effective treatment for cancer and other lethal conditions here at UW so that we can provide this incredible therapy that's going to work better year to everybody that needs it. But more importantly, to generate research data that we can share with the rest of the world to try and help people wherever they are survive cancer. Thank you so much.

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even more important reaction

>> Okay, thank you, Paul, for that wonderful talk. I want to now introduce our third speaker, Dr. Shigeki Miyamoto, another distinguished member of McArdle Laboratory of Cancer Research and professor of oncology. Dr. Miyamoto is an international expert in the study of NF-kappaB. This is a specific cell signaling pathway that contributes to cancer. He's a co-leader of the Carbone Cancer Center cell signaling program here at the School of Medicine and Public Health. And he's going to give a talk on the legacy of Charles Heidelberger, whose research at McArdle many years ago led to the first specific anticancer drug to ever be created with the goal of understanding how to prevent cancer or treat cancer. And then he's going to talk of new research, which is what we call transdisciplinary, which brings to bear people working on many different types of research areas. In this case, bioengineering and cancer biology to devise new ways of personalized medicine in the treatment of cancer. So, Dr. Miyamoto.

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>> Can you hear me? Is it on? Yes? Okay. Thank you, Paul. I'd like to talk about today, really, the legacy of Charles Heidelberger's discovery and his work developing a really interesting and important anticancer drug and our efforts to really carry on that legacy forward. So this is a picture of Dr. Charles Heidelberger. He joined the Department of Oncology at McArdle Laboratory for Cancer Research back in 1948. He was an expert of synthesizing chemicals. Chemicals that have impacts on biological systems. And within 10 years, less than 10 years, among many chemicals that he synthesized, one that really stood out was a chemical called 5-fluorouracil, 5-FU. Now, this one has a very strong anticancer effects. Why? Well, among many effects that this drug has, it inhibits replication of DNA, so thereby inhibiting growth of tumor. It turns out that this drug has been used for decades, still used currently, for treatment in breast cancer, colon cancer, and many other cancer types. It is listed on the World Health Organization list of essential medicines or chemicals. So his discovery in UW Madison had really wide region effects, not just in the US but worldwide, and it's still having such an effect currently. Okay. So I'm among the many, many awards and honors that he received for this very important and long list in work, in one of his award lectures he indicated, just like Dr. Lambert just mentioned, that he really emphasized the role of multidisciplinary approach. Really people with different expertise coming together to work on a very difficult common problem. Even though he was really successful, really rewarded with many, many outstanding achievements, he was still humble enough and to show he was frustrated with the fact that even this important drug sometimes works and sometimes does not work in patients. So this really gives one of the major problems of chemotherapy. It is the unpredictability. So for a given patient, one does not know whether the drug will work or will not work. Oftentimes, you're given a certain percentages. Okay, this will work 70% of the time, or perhaps 30% of the time. For a given patient, one does not whether it's going to work for you or does not work for you. Okay? So usually what happens is that patients given drugs, one has to wait and you find out. You're in the lucky group or not so lucky group. So you might ask, why wait? Why should we wait? Why can't we predict the clinical effects before we treat it? There are many, many research approaches and technologies that have been developed. For example, samples are analyzed for the presence of mutations. That's already been discussed. The presence of mutations can show what kind of altered pathways and processes are involved. Different proteins and cellular products can be also analyzed very carefully in a very detailed way. One can also take cancer cells and ask, why drugs really work? What drugs really kill? And a goal then is to use all of this information and ask, can we actually predict which drugs will really work for individual patients and which drugs will not work? And our lab has been involved in this last approach using the cancer called multiple myeloma. This is a type of white blood cell cancer that oftentimes grows in the bone marrow. The bone marrow that just Dr. Paul Sondel just described. Because these cancer cells produce a variety of factors, those factors can then stimulate degradation of bone. So this causes a lot of pain. As you can see in the X-rays, for example right here, these gray areas are pockets of cancer cells that are growing and degrading bones. Oftentimes leads to bone destruction, bone breakage, produces a lot of other problems in patients. It affects over 20,000 patients each year in the US alone, and over a thousand patients are dying because of this disease. Now, there are many drugs available as treatment of this disease. However, again, like in the 5-FU, we do not know actually which drug will work for which patient and which drugs will not work. So our team, the team Multiple Myeloma, team MM, really involves clinicians -- who will then collect samples from patients, and then some of those samples go to pathology lab to make sure that we're dealing with certain types of cancer, in this case multiple myeloma. Some of those samples come to our lab, and here is shown graduate student Chorom Pak, who is the one who really worked and pioneered the study that I'm going to be talking about shortly. Okay? Well, the problem was unlike one might think, when we started dealing with primary patient samples, we oftentimes thought that you can get a large amount of cancer cells. It turns out that's not the case in many cases. Oftentimes, the number of cells you're going to actually get is quite limited, quite variable, and the problem comes up then, how many drugs can you really test outside the patient? Another major, major, really biologically interesting and major problem is the association of cancer cells with other cell types. As Dr. Sondel mentioned, these cells live in bone marrow, and bone marrow is a place of many cell types. As you can see here, some of the red arrows are pointing to some of the cancer cells, but there are many, many non-cancer cells present in a sample. And this mixture are different for different people. So the question is, what are these other cells doing? Are they friends? Are they neighbors of cancer cells? Are they friends of cancer cells? Or are they enemies of cancer cells? Are they just sitting around doing nothing, or are they actually marginating? So we wanted to know that. So we said, okay, we need a new technology. Can we study in every patient small number of cancer cells and our cancer cells friends or buddies or potentially enemies in a device that allows us to investigate how the cancer cell is behaving in the presence of cancer drugs? So then we collaborate. As Dr. Paul Lambert mentioned, we are lucky enough to be housed in a new cancer building where bioengineering teams are also working towards their own cancer research activities, and we're able to work together to develop devices. These devices are very small. Very small but they're designed in a way that you can study not just cancer cells, but cancer associated normal cells. We can study them individually. We can study them together. On the right side, it's showing the actual sizes. These are quite small. Shown here as a quarter. You can see here these are really small, small microchamber devices. So what are we doing? Well, almost all current approaches used for cancer cells only. So you take the cancer cells out from patients, you expose them to drugs, you hope that that response will be replicating what you may see in patients. Well, it turns out it does not work so well. So we asked, what if you do the same thing but in the presence of these variable mixtures of cancer either friend or enemy? We don't know. It could be different for different people. So we say let's try the experiment. So here's what we found. Here's a given patient right here. What are we doing here? We're taking cancer cells and we isolate cancer cells and affect the same magnetic antibody trick that Dr. Sondel just described. We can isolate these cancer cells away from their buddies, put them in these micro devices, expose them to different amounts of cancer drugs. In this case, a drug called -- is used in anticancer treatment for multiple myeloma. What we're measuring then, after incubation for 24 hours, just one day, we then test how many cells are still alive. So when the number says one, this means cells did not die. So you can see in this case, when the cancer cells exposed to drugs by themselves, you see that as the drug concentration increases, eventually cancer cells start to die. Okay? That's what we expect. When we put the normal cells with them, what we did find in this particular patients' cases, cancer cells are protected. Okay? So this is typically what one expects. However, if you try this experiment with another patient sample, what one finds is completely opposite outcome. Here what we find is the cancer cells are very resistant. Not dying. But if you put their buddies, it turns out these buddies were enemies. Now the cells are dying. Okay? So what we found is that if you just measure, as I mentioned, just cancer cells themselves, the behaviors are very different compared to when the cancer cells are growing with their own non-cancer cell types. So when we look at many, many patient samples, and working with yet another set of collaborators. These are now biostatisticians, they can analyze data in a way that is completely unbiased. Okay? What we're finding is that a cluster of patient samples aggregated into one group. Cluster number one. What is it we're showing here? Well, zero means there is no change in cell death. Cells are living. Okay? Again, this pattern does not show when you look at just the cancer cells themselves. You have to do this with the presence of the own patient's normal cells the cancer cells are living with. Okay? And if you now look at the other categories, here the numbers are lower, in the minus. That means cancer cells died. Well, it turns out, we now bring in yet another collaborator to then to again look at the clinical responses of these patients, it turns out those that are not dying in these micro devices, these very tiny micro devices, these cancer cells are not dying, those patients were clinically non-responsive to the drug containing therapy. In contrast, those samples that are actually dying were responsive. Okay, so where are we? Well, we're still here.

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We're treating patients. We're waiting. We're trying to find out can we change this. We hope so. We're really trying to hope and trying to change this so that in the future by doing more research, more understanding of why those things are behaving the way they're behaving, why the cells are behaving differently, we hope that we'll be able to take every patient, study their cancer cells with their normal cancer associative cells and expose them to different drugs, identify which drugs will work with which patient, and then treat them with those drugs that will work. Okay? And we hope that this will help manage cancer patients better than currently done. Now, I mentioned a study from the two quotes from Dr. Heidelberger. And I've just shown an example of his legacy being still carried on. We're doing multidisciplinary approaches. We're asking the question, can we make the situation a little bit better? We have a team of cancer biologists, engineers, pathologists, clinicians, biostatisticians, and, most importantly, actually cancer patients are part of the team because without their support, without their donation of their samples, we are not able to do any research whatsoever. A very important point is that in fact all this research would have not been possible without the initial support from the cancer patients. Multiple cancer patients who donated, basically, seed money, an investment in us to start the research going. So here at UW Madison we're using these approaches to hope to develop a predictive chemotherapy test, and there are many, many other types of research such as this that are ongoing at the UW Carbone Cancer Center. So, thank you for your attention.

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>> Thank you, Dr. Miyamoto. Our last presentation is going to be done by Dr. Ruth O'Regan. We are very fortunate to have Dr. O'Regan here after a national search. We were very fortunate to recruit Dr. O'Regan from Emory University to come here and be the leader of our hematology and oncology section. Dr. O'Regan is a national leader in breast cancer research, and she is going to talk about the evolution of systemic therapy for early stage breast cancer, and talk about, as we've heard, some of the historical genius and what we think is ongoing genius of cancer research here at the University of Wisconsin. And she's going to describe two great examples of that, Dr. Paul Carbone and Dr. Craig Jordan, and the work and the landmark work they did in breast cancer. Thank you. >> Thank you, Howard.

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Good evening, everyone. And we're going to end talking, as we said, about breast cancer. And what I'm going to do is basically show you the very pivotal roles that some of the investigators here at UW have played in how we treat our patients with breast cancer today. And then later on we'll talk a little bit about some of the research that we're currently doing. Well, if you remember the video in the beginning, there was a reference to this in the clip that we saw. And that is the fact that back in the early part of the last century, the general hypothesis was that the more surgery done on the breast, the less likely you were to actually have a recurrence of your breast cancer. So William Halsted, who was a very famous surgeon of that time, proposed that by doing very radical surgery on the breast, where you remove not only the breast but also some of the chest wall and muscle underneath it, that that will cure cancer. The problem was that what happens, as you can see here, is women were left with these very big scars, a lot of pain, and the really bad news was that they were still relapsing from their breast cancers. So, unfortunately, this very radical surgery was not associated with a cure from breast cancer. Moving forward several decades later, another hypothesis came along. And this hypothesis was proposed by Paul Carbone, who you're all familiar with and who this cancer center is named after. And his idea was that rather than doing more surgery, what we should be doing is using some form of systemic therapy that goes everywhere in the body to cleanse the body of any residual cancer that might have spread away from the breast either before or at the time of surgery. So he did a small trial where he basically showed that by giving chemotherapy, which was the only systemic therapy that they had at the time, after surgery appeared to decrease the rate of redux from breast cancer. He then went on to coin a name that we use today, which the word of adjuvant, which translates from Latin to mean "to help." So, basically, his thought was that this adjuvant chemotherapy would be a little helper for the surgeon in that it would eradicate microscopic deposits of cancer that have broken away from the breast after surgery. Now, after convincing some surgeons in Italy to prove his point, it was really shown that if you take patients with early stage breast cancer and give them chemotherapy, they have a lower relapse rate than patients who don't get chemotherapy. This was an incredibly important finding because this is really the cornerstone of how we treat patients today. So as a breast oncologist, when a patient comes in to me with breast cancer, I always recommend some for of systemic therapy to them, be it, as we're going to talk about, chemotherapy or as we're going to talk about endocrine therapy. But this didn't just impact patients with breast cancer. It actually impacts patients with many other cancers, including lung cancer and colon cancer. Now, around the same time, there was another story going on, and this story related to the relationship that we understand partly now that there is a relationship between a woman's estrogen and breast cancer. And the whole association between estrogen and breast cancer actually dates back to 1895. Now, keep in mind nobody knew what estrogen was at this time point. And, certainly, the estrogen receptor we heard about earlier hadn't been discovered. It's a very interesting story because George Beatson was a surgeon in Scotland, and he was chatting to some farmers up in the Scottish Highlands who told him that if you removed the ovaries from cows, something happened in their capacity to lactate and also the quality of their udders changed. So there was something going on here that was connecting the ovaries to the breast. Now, Mr. Beatson, at the time, had three pre-menopausal patients with breast cancer. Based on what he heard from the farmers, he went ahead and said let's take your ovaries out and see what happens. And to his astonishment, the breast tumor shrank very dramatically. So he then went up to London, or went down to London rather, and he asked some of the surgeons in London to go ahead and try and repeat what he'd found. And the surgeons went ahead and had a series of women with breast cancer, and they treated them by taking out their ovaries. And they know that two-thirds of the cancers responded to breast cancer. So the good news was it was working in two-thirds of women, but the mysterious thing about this was why did it only work in two-thirds and why didn't it work in the other third? So this suggested there was something going on, and that breast cancers are not all the same, which, of course, we now know, but was referred to as Beatson's Riddle because we really didn't know exactly at this point why some patients benefited while others did not. So 80 years later, we kind of got the answer to the riddle. Now, between the time of Beatson working on and seeing what happened to breast cancer when he took out the ovaries and what I'm going to show you now, two very important things had happened. First of all, the drug Tamoxifen, which you've probably all heard of, was discovered. It was initially developed as a contraceptive but was found to have actually anti-estrogen effects on the breasts, so in other words, it appeared to oppose the effects of estrogen on the breast. The second key thing was that about 10 years before what I'm going to show you now, at University of Chicago, they discovered the estrogen receptor that we heard about before. So Craig Jordan was a person I had the fortune to work with for many years, for seven years in Chicago. He spent a lot of his pivotal years here at University of Wisconsin. And he was the one that solved this Beatson Riddle that I was describing to you. So what he did was a pretty simple experiment. He took some breast cancers, basically looked to see if they expressed the estrogen receptor, and what he found was that only the breast cancer cells that expressed the estrogen receptor were responsive to Tamoxifen. If the cancer cells didn't have the estrogen receptor, they didn't respond. So in other words, this estrogen receptor appeared to be binding to Tamoxifen, which then went ahead and basically caused the cells to die. Now, this may seem kind of simple and obviously in the era that we're in now where we have a lot of targeted therapies and we're always looking for proteins on cancers that we can target, this was a really very pivotal finding because it was the first time in history that a drug, Tamoxifen, its targeted estrogen receptor, and a cancer cell have been kind of joined together in this molecular logic. So, a very, very important finding and one that we use in the clinic today all the time. Now, when Dr. Jordan was at University of Wisconsin, he worked, really, on the development of Tamoxifen, which is a drug that you're, as I say, probably familiar with and has basically saved the lives of thousands and thousands of women. The first thing that he found was that not only did Tamoxifen appear to be able to treat breast cancer, it also appeared to be able to prevent breast cancer. So, if this is a rat model where you basically inject a certain chemical into these rats and they develop breast cancers, what Dr. Jordan showed was that if you gave these rats Tamoxifen, they didn't grow the cancer. So in other words, this drug was preventing breast cancer. Decades later, this was shown in a very large trial in which patients that were considered at high risk for developing beast cancer were treated either with Tamoxifen or with placebo, and what they found that yes, indeed, Tamoxifen did prevent breast cancer. It was about 50% less in the women that got Tamoxifen compared to the women who got placebo. And, again, this is something that we discuss with patients in the clinic, if we consider they're at high risk of developing breast cancer. The other thing he discovered was not so good. And that was, again, something we all know, that we've all noted over the past many years is that Tamoxifen is associated with an increased risk of uterine cancer. So he performed a very simple experiment where he took a mouse, he injected a breast cancer on one side of the mouse and a uterine cancer on the other side of the mouse. And what he found was that when you treated the mice with Tamoxifen, the breast cancer didn't grow at all. In fact, you can see there's no cancer there. On the other side the mouse where the uterine cancer was, however, the cancer started growing. So Tamoxifen was acting against estrogen on the breast but, essentially, like estrogen on the uterus. This has now been shown in many trials, and we all accept the fact that Tamoxifen is associated with a modest but definite increased risk of uterine cancer. So, again, another very pivotal finding that came out of his work here when he was at the University of Wisconsin. Now, in terms of where the focus of the breast program here now, it's got many focuses, but one of the main focuses is on triple negative breast cancer. And this is an area that I was involved before I came to University of Wisconsin. Now, triple negative breast cancer, you may or may not heard of, but it's a very important subtype of breast cancer because it doesn't express the proteins that are commonly seen in breast cancer, such as estrogen receptor that I talked about earlier, but also two other proteins, progesterone receptor and HER2/neu. And that's not a good thing because we have good drugs that target those particular proteins, but this particular type of breast cancer doesn't have those proteins that we can target with drugs. The other problem is that this is a very aggressive breast cancer and probably has the worst outcome of any of the breast cancers that we currently treat. Now, what we showed when I was in Atlanta, and other groups have shown as well, is that triple negative breast cancer appears to occur at a higher instance in younger women and also women of African American descent, so this is just looking at women in Atlanta under the age of 55, and what you see here is that in the very young women, under the age of 35, there's a very high rate of triple negative breast cancer whether they're African American or white. As they get older, once they hit around the age of 40, however, you can see that the white women, the instance of these triple negative breast cancer goes down, but it still remains very high in the African American women. Now, we don't know why this is. It could be genetic factors. It could be environmental factors. That's certainly something that there's a lot of research going on right now. So, as I said, these are aggressive cancers with a poor outcome, and the reason they have a poor outcome really is twofold. The first reason is that the only available treatment we have for these cancers right now is chemotherapy, but unfortunately it's ineffective in many cases. And there are researchers, for example Mark Burkard, who's trying to work out why certain cancers are resistant to certain chemotherapy agents. But the other issue that I alluded to is that there are currently not target agents that we can treat patients with triple negative breast cancer with. So we don't have a Tamoxifen for triple negative breast cancer, and that really is a huge problem. So I just want to highlight the work of two of the investigators in the breast program here at UW. The first one is Dr. Wheeler's lab, and what he's been focused on is a protein called epidermal growth factor receptor or EGFR. And this protein is known to be expressed on the surface of about 50% of triple negative breast cancers. Now, this is very good news when we found this out because there are several drugs that target this protein that we use in lung cancer. So we went ahead and we did some clinical trials expecting that these drugs would be just as effective in triple negative breast cancer but they weren't. Triple negative breast cancers, unfortunately, appear to be inherently resistant to these drugs. And what Dr. Wheeler showed was that in 20% of triple negative breast cancers, this protein, which is supposed to lie on the surface of the cell, actually lies within the center of the cell in the nucleus. And the drugs that target this protein have to target it when it's on, it has to be on the surface of the cell for these drugs to be able to work. So this, in a sense, basically explains one of the reasons why these drugs don't work in triple negative breast cancer. Then, very importantly, he was able to show that a leukemia drug, Dasatinib, was able to mobilize this epidermal growth factor receptor from the nucleus back onto the cell surface. So then you could basically target it with these antibodies because now it was on the cell surface where these antibodies work. So this is a very important finding, and with Kari Wisinski, we're hoping to start a trial where we'll actually be able to treat patients with triple negative breast cancer with a combination of these agents that target this EGFR protein with this leukemia drug. And the other investigator's work to mention is Vince Cryns, and, again, this is focused on triple negative breast cancer. And what his group has found is that there's a protein called alpha B-crystallin, which appears to be very important in triple negative breast cancer, and particularly in triple negative breast cancers that have spread to the brain. These cancers, as I said, are quite aggressive or very aggressive in their nature, and they do have a propensity to go to the brain, which is a very serious issue for patients. So what he showed was that this protein, if it's expressed in triple negative breast cancer cells, firstly impacts a patient's overall survival. So you could see when you have the protein, unfortunately the patients are more likely to die from the cancer than if they do not have the protein. But it's even worse if they have it spread to the brain because then their survival is very short if they express this protein compared to if they do not express this protein. And what he went on to show was that if you basically put this protein into triple negative breast cancer cells, it actually doesn't affect the way the tumors grow. It only affects the volume of the brain metastasis, so somehow, this particular protein is very important in whatever mechanism causes triple negative breast cancers to go to the brain. One of the problems is there isn't a drug right now that directly targets this protein, but what they've been able to show is that there's another protein that regulates this protein that we do have inhibitors against. So we're hoping that we'll be able to put a trial together looking at this approach in patients in the near future. And this is just acknowledging the UW team and the Emory team from before, and of course Dr. Jordan's laboratory. Thank you very much for your attention.

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