Researchers at The University of Kansas Cancer Center and Children’s Mercy Kansas City are joining forces to fight a cancer with a long history of low survival rates.
Osteosarcoma is the most common type of bone cancer found in children and teens. Nine out of 10 patients have “micro-metastasis,” meaning a small amount of the cancerous cells have spread from the original tumor site. Despite intensive chemotherapy, the survival rate for osteosarcoma has been stuck between 60-70% for the past 4 decades. Metastasized osteosarcoma reduces survival to less than 30%.
Through two projects, Tomoo Iwakuma, MD, PhD, The University of Kansas Cancer Center researcher and director of the Translational Laboratory Oncology Research program at Children’s Mercy, is working closely with Children’s Mercy medical oncologist Joy Fulbright, MD, and other cancer center members to identify a therapy to inhibit osteosarcoma growth specifically for patients who have not responded well to other therapies.
Children’s Mercy, an official National Cancer Institute Consortium partner of the cancer center, lends robust clinical expertise that dovetails with The University of Kansas Cancer Center’s strengths in basic research and drug discovery – a “dream” partnership, according to Iwakuma.
“Working together, we see both sides of research processes. I help ensure that what Dr. Iwakuma is doing in the lab translates to the clinic,” Fulbright adds.
Leveraging drug discovery tools
Current treatment for osteosarcoma involves up-front chemotherapy for 12 weeks, then surgery, followed by more chemotherapy. The team’s goal is to discover and develop an effective new drug to improve treatment outcomes.
“Tumor cells are smart and become resistant to a single drug treatment very quickly. We need to discover and develop new drugs that attack osteosarcoma cells without affecting normal cells,” Fulbright says.
To filter through the hundreds of thousands of compounds in existence and identify which ones may specifically kill osteosarcoma cells, the team uses High-Throughput Screening (HTS), a robotic sifting system. The results provide starting points for discovering novel, new drug candidates. The University of Kansas Cancer Center’s Lead Development and Optimization Shared Resource lends unique, fully integrated drug discovery capabilities including HTS, medicinal chemistry and drug synthesis to support researchers through the discovery process.
“We screened more than 150,000 compounds for activity against our osteosarcoma target, identifying ‘hits,’ or a focused set of potential active compounds,” Iwakuma says.
Working together, we see both sides of the research process. –Joy Fulbright, MDChildren's Mercy medical oncologist
From there, the team conducted further tests and honed in on a single, novel compound that killed a particularly aggressive line of canine and human osteosarcoma cells. Compound activity in canine osteosarcoma cell lines were evaluated in parallel with human osteosarcoma cell lines. Biologically, the characteristics of the disease in dogs is remarkably like the disease in humans. Iwakuma explains that dogs are 15 times more likely to develop the disease, and studying the efficacy and safety of promising new treatments in already-sick dogs provides valuable insight into how humans may respond.
Iwakuma’s drug target is mutant forms of the p53 protein. In its normal state, the p53 protein, known as the “guardian of the genome,” regulates cell growth. When mutated, it can contribute to metastasis, drug resistance and cell growth.
“We all have active p53 in our genes. However, cancer cells can lose p53 activity. One of the active compounds we’ve identified only kills the cancer cells that lack p53 or contain mutated p53,” Iwakuma says. “In other words, this compound specifically targets cancer cells and does not affect normal cells. At that moment, I knew we had a promising drug discovery project.”
Initially supported by a grant from the Midwest Cancer Alliance and propelled forward with a follow-on grant from Braden’s Hope, a local nonprofit organization, the team is now studying the compound’s mechanisms of action in killing canine and human osteosarcoma cells.
“The loss of p53 protein makes cancer cells more sensitive to the compound. But why and how? So far, we know this compound somehow causes DNA damage that is not efficiently repaired in cells lacking p53. The damage accumulates over time, leading to death of cancer cells,” Iwakuma says.
Although the team is optimistic about the compound currently being studied, parallel efforts are focused on discovering and developing improved drug candidates.
“We have a strong starting point for discovering novel, new agents that target mutant p53 proteins,” Iwakuma says. “It’s a unique advantage to have a team encompassing so many skills, including drug discovery experts who bridge the critical gap between the lab and the clinic. I couldn’t be more excited.”
From the earliest nugget of an idea at the bench to drug development and clinical trials, the collaboration between the cancer center and Children’s Mercy convenes the best from each institution, including biologists, oncologists and translational scientists.
“Working together, we see both sides of the research process,” Fulbright says. “It’s a good back-and-forth partnership that we hope will result in new treatment options for osteosarcoma patients.”
Bench to Bedside: Sarcomas
Speaker 1: Welcome to Bench to Bedside, a weekly series of live conversations about recent advances in cancer, from the research bench to treat at the patient's bedside.
Alex Goodwin: It's so rough that sometimes I feel like my dreams shatter up into tiny pieces. So hard on me.
Speaker 3: At just nine years old, Alex Goodwin was in the fight of his life after being diagnosed with bone cancer. He underwent chemotherapy treatments, which were not enough to kill the cancer.
Dr. Rosenthal: Alex had a cancer, a very rare cancer, actually, called a Ewing sarcoma. It involved the entire femur, the entire thigh bone, all the way from the hip all the way down to the knee.
Speaker 3: That's when Alex and his parents traveled from the UK to receive lifesaving treatment here at the University of Kansas Cancer Center. Were Dr. Howard Rosenthal replaced Alex's existing bone with a grower bone.
Dr. Rosenthal: Then we put in a noninvasive growing, or expandable prosthesis. This is an artificial femur-
Speaker 3: This technology allows doctors to adjust the prosthesis noninvasively to grow as Alex grows. Now nearly two years after the procedure, Alex has his spirit, and his hair back.
Alex Goodwin: I think it's great. I used to be like dad's hair, but now it's straighter.
Jeff Goodwin: The ultimate goal is obviously to get him walking independently again, which is completely [inaudible 00:01:44], apart from where we were, when we weren't even going to save his life. So it's amazing.
Maria Goodwin: And it is hard to watch for me as a parent for my husband as well, but it has to be done. That is the only way. There's no point having a new leg, if he's not going to use it.
Speaker 3: Finally, up and out of his wheelchair, Alex was able to show Dr. Rosenthal how he is starting to walk even without crutches.
Dr. Rosenthal: Push down. Push down hard. He's a champion. His disposition is always amazing. We come out of seeing him and always have a smile on our face.
Alex Goodwin: I just want to have a normal life like everybody else when this is over, and I can walk. And I won't feel like I don't have a mechanical bone. I will just feel like all the normal human bone.
Maria Goodwin: Dr. Rosenthal seems to be happy with what we've done, so we are going to step it up again, and continue, because at the end of the day, he's got to run down that beach one day. It's a big dream.
Dr. Roy Jensen: Hi, I'm Dr. Roy Jensen, Director of the University of Kansas Cancer Center. With me today is Dr. Howard Rosenthal, an orthopedic surgeon who specializes in sarcomas, and Dr. Benjamin Powers, who is a medical oncologist whose focus is on sarcoma treatment. So first of all, sarcoma is a pretty rare disease. Exactly what type of cancer is a sarcoma?
Dr. Rosenthal: So that's correct, sarcomas are a group of a rare group of cancers, typically derived from the musculoskeletal system, whereas most cancers that people hear about come from organs that have glands in them, or surface organs, things like that. Sarcomas come from the muscles, the fat, the nerves, the connective tissues, and the bones. Places where people don't typically think cancers come from.
Dr. Roy Jensen: So tell me about the team of folks that's necessary to put together a treatment plan for a cancer sarcoma patient.
Dr. Rosenthal: Because of the rarity of these cancers, a good sarcomas center must have a group of dedicated physicians consisting of orthopedic oncologists, surgeons, medical oncologists, radiation oncologists, pathologists, radiologists, and even more, that really are dedicated to the treatment of sarcomas. You have to perform a lot of these cases. You have to be able to treat a lot of patients to understand how sarcomas behave.
Dr. Roy Jensen: So Dr. Powers, what should a sarcoma patient look for when they're choosing an institution to be treated?
Dr. Powers: Yeah, I think a lot goes into it, but certainly expertise, like Dr. Rosenthal just mentioned, and a true team approach, multidisciplinary approach. If you look at national guidelines for treatment of a sarcoma, they consistently recommend a multidisciplinary team that is familiar with sarcomas. I think that's one of the things that make sarcomas unique, is it really can pop up from head to toe. And so sometimes neurosurgeons need to be involved. Sometimes orthopedic oncologists obviously are a huge part of it. Sometimes we get surgical oncologists or urologists involved. So it really can be all sorts of specialists that are part of the sarcoma team.
Dr. Roy Jensen: So I'd like to ask both of you from your perspective, tell me about the evolution of sarcoma treatment over the last 20 years. Because it's really been amazing to watch as my career's gone by.
Dr. Rosenthal: Alright, so the whole concept of what we consider limb preservation, which is the modern era of the treatment of sarcomas started in the late 70s, early 80s. And that consisted of the ability to image, diagnose, and then resect, and reconstruct. Take out the cancer surgically, and be able to perform a limb salvage surgery, or saving a limb using various reconstructive techniques. Back in the 80s and 90s, even up to 2000, most of those techniques were custom design prostheses that required a significant amount of time to make, thereby giving our medical oncologists time to be able to use chemotherapy to try to shrink the tumor down. And then from the 2000s on to today, we've advanced just unbelievably fast in that technology of reconstruction. In addition, our ability to diagnose has gone from looking at these tumors under a microscope and linking them, or gathering them into one diagnostic consideration. Something that used to be called a malignant fibrous histiocytoma, to now, where we have more than 80 different types of diagnostic considerations with treatments that we can gear towards each one specifically more tailored treatment
Dr. Roy Jensen: And Dr. Powers?
Dr. Powers: So about 30 years ago, was when we first started using lots of chemotherapy for bone sarcomas, Ewing sarcomas, osteosarcomas. And it really revolutionized the survival curves in kids and adults with bone sarcomas. Twenty years ago was really when targeted drugs started coming out outside of chemotherapy, 1998 was Herceptin, early 2000s was Imatinib or Gleevec. These are targeted drugs that aren't considered chemotherapy, and have really revolutionized the treatment of breast cancer, and chronic myelogenous leukemia respectively. Now we are using these same type of targeted drugs like Imatinib for rare types of sarcomas, Dermatofibrosarcoma protuberans is a cancer that's very sensitive to a Imatinib, GI stromal tumors are very sensitive to Imatinib, that's just one of the targeted medicines that is really kind of changed how these last 20 years have gone for treatment. There are lots of inhibitors that really aren't considered chemotherapy now that I could keep mentioning, but that's really where we're going.
Dr. Roy Jensen: So one thing that's dramatically different about sarcomas in comparison to most of the diseases that many people consider when you're talking about cancer, is the incidence. Could one of you tell us about the number of cancer cases that are seen nationally, and then perhaps where we stand as an institution?
Dr. Powers: They make up about 1% of cancers in adults. So again, when you start breaking down the 80 different types, each one of these types of sarcomas is extremely rare. In children, the incidence is about 7% of cancers. So it's a little bit more prominent in the pediatric population, but still not common.
Dr. Roy Jensen: And then how many do we see at KU?
Dr. Rosenthal: So we do around 180 to 200 soft tissue sarcomas a year, and about 20 to 30, maybe 40 bone sarcomas a year here at KU in our Sarcoma Center.
Dr. Roy Jensen: And that's a very large treatment facility for sarcomas.
Dr. Powers: That is considered one of the largest actually sarcoma centers in the country. Yes.
Dr. Roy Jensen: Right. Typically, I mean I've seen primary care physicians who may have one or two or maybe never even see a sarcoma.
Dr. Rosenthal: That's correct. The average physician will see maybe one to two in a lifetime. The average orthopedic surgeon, because most of these do come from referrals from orthopedic surgeons, will see between two and three in a lifetime. So they are considered very, very rare cancers.
Dr. Roy Jensen: Right. So if you're just joining us, we're here with sarcoma specialists, Dr. Howard Rosenthal and Dr. Benjamin Powers. And we're discussing advances in sarcoma treatment. Remember to share this link with people you think might benefit from our discussion. Use the hashtag #benchtobedside. So Dr. Rosenthal, as you've mentioned, the standard of care for sarcoma treatment has really changed over the last two decades. What has been your role, and KU Cancer Center's role in helping advance some of these treatments?
Dr. Rosenthal: So first of all, we've developed the sarcoma team, which is really the most important part because the treatment for sarcomas is truly individualized, not just to the type of sarcoma but for the patient themselves, to the location of the sarcoma in the patient. Obviously, to the stage, and the grade of the disease. So while surgical resection may be a primary treatment for it, that doesn't necessarily mean it's going to be the only treatment, and certainly doesn't mean it's going to be the first treatment. In that situation, we talk to each other weekly. We have a tumor board biweekly where we discuss each individual patient and what's the best treatment options for that patient.
Dr. Powers: And we've established a multidisciplinary sarcoma clinic. It's going on now two years now where I will go over to Dr. Rosenthal's clinic, Dr. Massey, one of our radiation oncologist will meet us over there as well. And so these patients, with newly diagnosed sarcomas, will get to see three specialists in one clinic visit, radiation oncology, medical oncology, and orthopedic oncology. It really is a nice thing for patients who are coming from Arkansas, or Nebraska, or western Kansas, to see and develop a plan all at the same time.
Dr. Rosenthal: And because of the rarity of the cancers, there's no one city, for example, that has an abundance of sarcomas. So most of our patients actually do come from a very wide swath of the Midwest. To be able to see all of us at the same time, develop, formulate that plan of treatment, and institute it right there in one stop, one stop shopping type of treatment for that cancer, personalized care, is obviously very important for the patient.
Speaker 1: So why is it so critical to get the diagnosis correct for sarcomas, and distinguish them from other types of cancers that patients may be diagnosed with? What is the key aspect of that?
Dr. Rosenthal: So I like to say you have to think like the sarcoma. They behave differently than carcinomas, or other cancers. They spread differently, and you have to get ahead of them. Unfortunately, there are no risk factors, there are no signs or symptoms that denote that a patient has a sarcoma. There are no blood tests. So we have to be able to think like that sarcoma and know how it's going to behave. And that's going to determine how we resect, or how we remove the tumor, if we're going to treat it with chemotherapy first in order to eradicate distant metastasis that might be present, or how we're going to utilize radiation as an assistant type of a treatment, or an adjuvant treatment to try to make that surgical result in better performance type of result.
Dr. Roy Jensen: So one of your more famous patients on your service, actually came to us from England. Could you tell us a little bit about that situation in terms of all the different types of treatment that that young man had? And how he's doing right now?
Dr. Rosenthal: Sure, so this is a good example of some of the technological advances in the past decade, and maybe even two decades. But mostly just in the past two years. Alex had an osteosarcoma, a malignant bone cancer of the femur, of the thigh bone. It extended from the knee up to the hip, and then also into the pelvis a little bit. So it was a quite extensive type of cancer. That obviously requires surgical resection. He started getting his treatments as chemotherapy in England. But they didn't have the types of drugs, and the type of frequency that we would need to give those drugs in order to complete a very adequate, successful type of pre chemotherapy, or presurgical chemotherapy treatment. So the family came to the United States, came to KU, and we initiated repeat neoadjuvant chemotherapy. And then performed a two-staged reconstruction of the limb, by removing the entire Femur and replacing it, which has all the cancer within it, as well as the cup portion of the pelvis, which had the cancer components in it, with a noninvasive limb lengthening prosthesis. Now what that means, is he's 10 years old. He has a lot of growth left to go, a lot of growth potential. And if we put a metal piece in his body, a metal prosthesis in his body, that's not going to grow. So a noninvasive limb lengthening prosthesis allows us to put that limb after we close and after we successfully reconstructing the limb, into what we call a mini MRI [skin 00:14:58]. It's something I can carry, put over his leg, I call it the magic wand. And after about 10 to 20 minutes, we actually lengthen his leg without having to do repetitive surgeries. So Alex actually comes back to the United States every two months now he's well past as chemotherapy, he's got his hair back. He's free of disease. And we're keeping his limb lengths equivalent by lengthening it as he grows. So his operated leg keeps up with the non operated leg, and its growth.
Dr. Roy Jensen: That's such an incredible story. And like you say, does an amazing job of describing all of the advances that have taken place in this disease over the last 20 years. So what would you like for most of our listeners today to take away from this discussion of sarcomas? And I'll start with you, Dr. Rosenthal.
Dr. Rosenthal: Well, the main, I think, take home message is awareness of the disease. Once again, because of the rarity, there are no support groups. We're not going to see commercials or television shows about sarcomas. So a patient who has a soft tissue mass, and I don't mean to suggest that every soft tissue mass should be a sarcoma because the reality is, is they're not. But for both patients and physicians, if it doesn't feel like what you think it should feel, see your doctor. For the physician, if it doesn't feel like a lipoma, a benign fatty tissue tumor, if there's something to suggest something else, that we shouldn't blow it off and not worry about it. There are tests that we can do. We can make the diagnoses very, very clearly. Just to be aware of the disease process.
Dr. Roy Jensen: Dr. Powers.
Dr. Powers: And I would say probably the three things that I would want patients and providers to know about our team, is the awareness as Dr. Rosenthal said, but communication and care. I really do think that we have a wonderful team that actually likes to be with each other and quiz each other, and test each other on a what is going to be the absolute best care plan for this patient. And if I can't provide the trial, or chemotherapy that we have, then we'll certainly explore other options. But for the most part between our radiation teams, our surgical teams our medical oncology teams, we really are a great communicative, caring team.
Dr. Rosenthal: We attend as a group, national and international conferences and meetings. We present at these meetings. We teach the other physicians also about it. So we're really up to the technological aspects of it, the state-of-the-art chemotherapy treatments, and radiation therapies that we have available. And that's something that I think we're very proud of. Again, that comradery. I'm not just sending a patient to Dr. Powers for chemotherapy, we're treating that patient together.
Dr. Roy Jensen: I think one message that's come through for me today is how important it is to have that team in place. And when a patient starts down this path, they really need to get to a high volume center with a multidisciplinary team in place from the very beginning. It's not a disease for the faint of hearted, in terms of the treatment path. And it really requires world class experts to be there at the very beginning when you're making critical decisions on this. We're so proud of what you guys do, and Alex's story is just a great example of that. And if people are interested more, they can certainly visit our website, and see his stories. But that's all for today. Thank you very much for being with us. To learn more, please visit KUCancerCenter.org/sarcoma. Be sure to tune in next Wednesday at 10:00 AM. Thanks for watching.