Rein in Sarcoma has awarded $40,000 in new sarcoma research grants to Children’s Minnesota and the Mayo Clinic. The grants were announced during the recent virtual Fall Fundraiser. The RIS Research Committee reviews the top proposals brought forward by each institution’s evaluation committee, and in turn recommends final awards to the RIS Board of Directors for approval.
Children’s Minnesota
“DICER1-related Genitourinary Sarcomas” | $15,000
Dr Kris Ann Schultz
Principal Investigators: Kris Ann P. Schultz, MD, pediatric oncologist
Lay Summary: DICER1-related sarcomas include pleuropulmonary blastoma (PPB), renal sarcoma, ovarian, cervical and uterine sarcoma, and a newly-described tumor type, PPB-like peritoneal sarcoma which may arise from peritoneal structures. We have preliminary data suggesting that in PPB, quantitation of circulating tumor DNA bearing DICER1 “hotspot” mutations may provide a way to measure tumor burden and provide a strategy for early diagnosis, especially for children with recurrent disease. In this proposal, we will leverage our prior Rein in Sarcoma funding and R01-funded existing PPB-related research activities and extend these to include additional DICER1-related sarcomas. Development of this additional collated data source is the next necessary step toward our goal of validating ctDNA for clinical use in children and young adults with DICER1-related sarcomas.
Mayo Clinic
“Targeting the Immune Checkpoint B7-H3 for the Treatment of Rhabdomyosarcoma.” | $25,000
Principal Investigator: Dr. Fabrice Lucien-Matteoni, PhD, Senior Research Fellow in Urology Co-Investigators: Dr. Haidong Dong, MD, PhD, Professor of Immunology, a world-renowned immunologist and Dr. Akilesh Pandey, PhD, Professor in Laboratory Medicine and Pathology and Director of the Proteomic
Lay Summary: Rhabdomyosarcoma (RMS) is the most common soft tissue tumor in children, with nearly 20% of children presenting with locally aggressive and/or metastatic disease. A fundamental problem with this disease is the lack of effective and tolerable therapeutic regimens. Current protocols including surgery, radiotherapy and chemotherapy are extremely toxic and may lead to multiple deleterious long-term effects. Moreover, a significant percentage of patients tends to relapse and for those patients, life-expectancy is less than 5 years.
Our group is dedicated to help develop more effective and more tolerable treatments for rhabdomyosarcoma. In the past year, we have screened for proteins enriched in RMS tumors compared to normal muscle in the intent to identify new therapeutic targets for the treatment of RMS. We have discovered the molecule B7-H3 as an important mediator of tumor progression. B7-H3 protects tumor cells from being attacked by immune cells. We have found that loss of B7-H3 expression leads to tumor regression through an effective antitumor immune attack. In this proposal, we intend to understand how B7-H3 protects RMS tumors from the immune system. Additionally, we will initiate the development of an antibody-based therapy that inhibits B7-H3 function and boosts anticancer immune response. This work will lay the foundation for the immediate clinical utility of developing clinical trials to assess the efficacy of B7-H3 blockade for the treatment of refractory and relapsed RMS.
These grants are made in addition to research grants to the University of Minnesota made in January of this year.
University of Minnesota Professor and medical oncologist Keith Skubitz has been treating people with sarcoma cancer for over 20 years. Maybe, he is your doctor. What he really seems passionate about is finding ways for science to help doctors deliver better treatments to their patients. This can mean anything from more effective drugs to portable pumps, which allow patients to take their chemo home.
Dr. Skubitz received his medical degree from the Johns Hopkins University, then completed his Internal Medicine training at the University of Minnesota. He took a fellowship in Clinical Pharmacology at Johns Hopkins and returned to Minnesota for his fellowship in Medical Oncology. Here he has stayed. Since 1988, Dr. Skubitz has led the University of Minnesota’s medical oncology treatment efforts for adult sarcoma patients.
Better Patient Care
One of the first things he did was to study the possibility that chemotherapy could be delivered differently. Drugs like ifosfamide had been given to patients in one or two big infusions, over several hours in the clinic. Dr. Skubitz thought it made more sense to deliver the drug slowly, over many days, by a continuous drip. He said “you knew from high school chemistry” that this might make the drug more effective. For one thing, the long steady drip could increase the chances the drug would be there in the body, active and available to hit new cancer cells as they were turned out by the tumor, day after day. This also could lessen side effects, because people would not need to absorb so much of the drug at once.
In about 1980, new technology made this option possible. Portable pumps could deliver a slow continuous drip to patients, even while they moved around freely or stayed at home, carrying their pumps in little packs. With a colleague, Dr. Skubitz studied this method and found that it worked. They published their findings, and many other doctors have followed the same approach.
Finding Better Medicines
Dr. Skubitz says his work is “certainly very interesting,” and sometimes he and his colleagues have “very satisfying results.” It is hard, however, that the treatments don’t always work. For many patients, “eventually, they stop working.” This is a “high stress” time.
One way to improve the situation is to find better medicines. Of course, this could mean making something totally new. But it also could mean making a new match, between an existing drug and an aggressive disease. University researchers have been part of just such a solution for giant cell tumors of the bone. These tumors usually do not kill people, but they can grow aggressively and there have not been good treatment options. Doctors use surgery and radiation when possible, but good results can be hard to get and even then, the tumors often grow back. It appeared to Dr. Skubitz and his colleagues that an antibody developed for osteoporosis might target these bone tumors. A small initial study showed that the drug did help. The University now participates in a world-wide follow-up study to consider the best dose and length of time to use the drug, which is seen as a very promising treatment.
Along the way, doctors also learned more about how tumor cells “talk” to normal cells. In this disease, tumor cells make a protein that recruits normal cells to come nearby and make something – call it factor x – that the tumor itself needs to thrive and grow. The drug works by blocking this protein, interfering with the tumor’s call for normal cells. With fewer normal cells stopping by to donate factor x, the tumor can’t grow so well anymore. Sometimes, it even dies.
Using New Science
Cutting-edge science clearly motivates Dr. Skubitz. On the list of scientific articles he’s written, there are many about genes. Dr. Skubitz tries to understand what tumors are telling us through the unique collection of genetic mutations and expressions they contain. When asked if the study of genetics will turn out to be an important thing for patients, Dr. Skubitz did not hesitate. “Absolutely,” it will.
Of course, genetic work could help doctors develop more effective treatments, targeted directly at the mistakes or pathways that allow the cancer to grow and spread. Even without a cure, genetic work could help doctors predict how dangerous a cancer will be. “Absolutely, definitely” it matters to know which cancers are most likely to be dangerous. This will affect the choices doctors make about treatment. Patients with less dangerous tumors could be spared the more intensive treatments; patients facing tougher battles could receive the most aggressive options.
Just this month, Dr. Skubitz was at a national cancer conference presenting results from a study that uses genes to help doctors separate the more aggressive cancers from the less dangerous ones. This work grew from one of RIS’ first seed grants. Years ago, University researchers including Keith Skubitz and his wife Dr. Amy Skubitz received a grant to identify the genetic signatures that might help doctors predict what cancers would do. The University’s tissue bank and the RIS grant allowed them to begin. Eventually, they found gene sets that appeared to break sarcoma cancers, ovarian cancers and kidney cancers into two main groups. They did not have enough information about what happened to the patients, though, to allow them to test the idea that the two tumor groups acted differently in people. Recently, the Skubitzes collaborated with researchers in Sweden and Denmark, who did have access to good follow-up information about patients. This work confirmed the sense that different gene sets appear in tumors that are more aggressive than in those less likely to be dangerous.
Another RIS-funded project that Dr. Skubitz works with is the clinical trial designed to test whether PET scans can show us which tumors are responding to chemotherapy. This is “quite neat,” because it may suggest better measures to test drug response. Using traditional methods, it could look like “you killed it off really well,” but then sometimes the tumor comes back. Doctors believe this may be due to the survival of a select group of deadly cells, sometimes called “cancer stem cells,” which may be great at hiding from toxic drugs or blocking their effects. If doctors could tell early on which tumors are being affected by a drug, they could spare patients who are not responding by stopping the drug and could switch them sooner to a potentially more effective option.
Always Surprising
When I asked Dr. Skubitz if there was anything else he thought we should know, he said this sounded an awful lot like the “classic internal medicine question.” Do your visits end with this invitation? Apparently, from the other side of the table, it is “striking” what patients will mention in closing. The doctor may have covered four or five major problems, and “you may think you know why they’re there,” but what’s really of concern to the patient may be something that’s “not even on your radar screen.” It’s surprising what you hear.
Hopefully, most of us can be thankful that our physicians do ask us for our concerns, and will listen for the surprise.
Logan Spector is not a medical doctor, but he does have the opportunity to talk with families as part of his research work. In his experience, the first question asked by parents whose children have been diagnosed with cancer is: What’s going to happen to my child? The second question is: Why did this happen to my child? Epidemiologists like Dr. Spector are “here to investigate the why.”
Back in 2004, a small seed grant from Rein in Sarcoma helped Dr. Spector support a successful application for funding from the National Institutes of Health. NIH funding allows him to study the connection between osteosarcoma and certain genes. The entire field of genetic epidemiology has been revolutionized, with the possibilities changing dramatically in just the last decade. In other work, Dr. Spector uses new technology that could increase the chances of finding key connections between troublesome genes and aggressive cancers. The University of Minnesota, where Dr. Spector is an Associate Professor, is “a great place to study pediatric cancer.” It’s not quite the life led by Colonel Sam Daniels, but it suits him well.
A Beginning
At The College of William and Mary, Logan Spector studied biology. For his life, Dr. Spector sought a field where he could use this science without being tied to a lab. Epidemiology offers these possibilities. For a time, Dr. Spector was intrigued by Colonel Sam Daniels, the character played by Dustin Hoffman in the 1995 movie “Outbreak.” But then he discovered that Hoffman played a virologist, not an epidemiologist. What’s the difference? Virologists chase down viruses, sometimes deadly and always contagious. Not the best fit for a man who wanted to have a family one day. And not the study of people, which is what Dr. Spector found really interesting.
Epidemiology is the study of people. Groups of people, put into categories and then compared. Researchers look for the factors that make a difference. Is one group more likely to suffer disease than another? If scientists can find out why, then we may be able to prevent the harm. Even when this is not possible, it can be helpful to know our chances. And in cancer research, naming the targets can lead to break-throughs in treatment.
When I think about break-throughs in treatment, I tend to think of fancy new drugs. But here is a more stealth example, at least for those of us who don’t do this for a living: Scientists have discovered that children who have one particular version of a certain gene will face a great risk of getting sick from one of the main treatments used for acute lymphocytic leukemia. Because they know this, doctors now can test their patients to look for this gene. If the children have the version that places them at risk, doctors can lower the dose of the drug, and lower the chance the kids will get sick. Steps like these can lead to real differences in many lives.
Making this difference seems to call Dr. Spector, who received his PhD in Epidemiology from Emory University in 2002. He began with an intention to work with infectious disease. His dissertation led him to childhood leukemia, however, and he has worked with pediatric cancers ever since.
Calling for Investigation
Like many of his colleagues, Dr. Spector is drawn to challenging and important questions. After he arrived at the University of Minnesota, one of his first assignments was to write a book chapter on childhood cancer. So he dove into the literature. There he discovered osteosarcoma and Ewing’s sarcoma, two cancers that were “ripe for study.” In osteosarcoma, there was “this very strong clue” that the cancer “mirrors puberty almost exactly.” Girls peak earlier than boys, both in their age for getting the cancer and in their age for puberty. Boys peak later, and their peak is higher than girls. Their pubertal growth spurt is longer and more intense – they get taller and bigger, on average, than girls – and they also have higher chances of getting osteosarcoma.
Ewing’s sarcoma arises almost exclusively in children of European descent. It also is strongly associated with hernia. This means that children who have certain kinds of hernias are more likely to get the cancer than would be expected just by chance. And don’t think, here, about those hernias your friends may get from lifting too much weight. The hernias that are linked with Ewing’s sarcoma are inherent weaknesses in tissue structure, affecting for example the umbilical cord, the diaphragm or the intestines. People are born with these weaknesses. This suggests a possibility that Ewing’s sarcoma could be caused by things that happen before children are born.
Basically, there was this “grab bag of things that did not fit well together,” which, to Dr. Spector, was “collectively calling for investigation.” And so he has investigated, with fine mentoring from Dr. Julie Ross, who brought him to the University through a research training grant and who continues to serve as his mentor today.
Revolutionary Advances
If you think of the human genome as a book, the Human Genome Project found the first letter of every sentence, and the period at the end of each sentence. Next, scientists began to fill in every seventh letter of each sentence. Now, scientists are in the process of discovering every letter in every sentence. Dramatic changes have occurred in this field, even since Dr. Spector began his work in 2002.
Several years ago, when scientists wanted to look for certain genetic changes that might be important for cancer, they needed to decide up front. Using the clues they could find, researchers would name the genes they were going to study. The problem with this method is that we people have about 30,000 genes. The ways they combine together, and the things that can go wrong, are almost too many to count. So the chances of hitting on just the right connection, between bad genes and bad cancers, were not great. The studies based on these predictions ended up having a fairly poor track record, as scientists learned that “we don’t know as much as we think about what might be relevant.”
Enter the Genome Wide Association Study, which now allows scientists to “put a genome on a chip and get back a million base pairs.” I’m not really very sure what this means. But I do understand that what it promises is a much better ability to compare information across people and cancers, and to figure out what really matters. Dr. Spector’s current work includes this kind of research for both osteosarcoma and Ewing’s sarcoma.
“Those of us who’ve been paying attention,” notes Dr. Spector, have heard a lot of hype for the last 10 years about the benefits of personalized medicine. The benefits “have not materialized as fast as we’d like. But it will happen.” Particularly for childhood cancers, the benefits will come.
We await this future. And are glad that bright young minds continue to engage the clues.
Dr. Subramanian has been researching sarcomas since 2003. Although only few funding resources are available for sarcoma research compared to other cancers, Subramanian is drawn to the field. Sarcomas often strike children and young adults, who have so much life left to experience. Subramanian would like to discover ways to help these people. His own proposed title for this interview? “Let’s make sarcoma the disease of the past.”
Researchers look for tools that will allow doctors to better treat their patients. One recent example from Dr. Subramanian’s work was the discovery of a biomarker to distinguish between synovial sarcomas and malignant peripheral nerve sheath tumors. These two cancers can look very similar on imaging scans and under the microscope, but the best treatment for each type is very different.
Through your support, Rein in Sarcoma helps create the energy that sustains scientists like Dr. Subramanian. We thank you for this, and look forward to our future work together.
Dr. Randy Hurley is a hematologist/oncologist at Regions Hospital and Medical Director of HealthPartners’ Cancer Care Program. He has been involved with Rein in Sarcoma since its onset. He was Karen Wyckoff’s medical oncologist and attended the very first RIS event with her. He has since attended nearly every Party in the Park and maintains a close relationship with Pete and Sue Wyckoff.
Dr. Hurley graduated from the University of Wisconsin – Madison with an undergraduate degree in Pharmacy. Before and during medical school, he worked as a clinical pharmacist on the hematology-oncology ward at the University of Wisconsin. He completed his internal medicine residency and chief resident year at UW as well. During this time, he was involved in basic science research on extracellular matrix proteins.
In 1991, Dr. Hurley came to the Twin Cities, where he completed a hematology-oncology fellowship at the University of Minnesota and spent an additional year investigating hematopoietic stem cell adhesion to extracellular matrix proteins. He has been at Regions Hospital for over 20 years, the past nine of which have been spent as the Medical Director of HealthPartners’ Cancer Care Program. Dr. Hurley also holds a special interest in global health. He is board-certified in tropical medicine and has had an ongoing health care project in Tanzania for 15 years.
Early influences in his career drew Dr. Hurley towards a career in hematology-oncology. Working with cancer patients, he says, is both an art and a science. His career provides both inspiration and challenge on a daily basis. According to Dr. Hurley, because sarcomas are so rare, many primary care physicians may not be familiar with how they present. This poses a unique health care challenge.
Dr. Hurley is leading a RIS pilot project at Regions Hospital and HealthPartners to increase awareness of sarcoma cancers among medical providers with the goal of significantly reducing the amount of time between the onset of sarcoma symptoms and a proper diagnosis. As a part of this effort, he is heading up a RIS Task Force with Robert Gao, 2016-17 Sarcoma Scholar; Brittany E. Mathews, Senior EPIC Specialist for HealthPartners Oncology Service Line; Tim Michalski, CEO of Point of Care Decision Support, Jay Syverson, President of Point of Care, Decision Support; Christian Ogilvie, MD, RIS Board of Directors; Pete and Sue Wyckoff. The Task Force is seeking to develop an electronic medical record alert to help Primary Care Physicians to recognize and appropriately evaluate suspicious soft tissue masses at an early stage. This pilot project is a key part of the efforts of the RIS Hallie Anne Brown Educational Initiative.
I once heard University of Minnesota Associate Professor and medical oncologist Brenda Weigel referred to as “the hope doctor.” It is easy to see why this could be so. Dr. Weigel radiates a sincere and vital hope, fueled by her research seeking better cancer treatments but grounded in her experience treating cancer patients. “Far too often,” she has faced situations where there was “nothing else to do” for patients. But she also has seen recoveries in recent years that would have been unimaginable before.
Even more exciting developments are on the horizon. Dr. Weigel would like to recognize the Wyckoff family and all those who have helped Rein in Sarcoma, for the huge impact the group has had in moving the University to develop what is now becoming one of the premiere sarcoma programs in the country.
The Accidental Oncologist
It may surprise you to discover that Dr. Weigel “was not one of those people who knew from the beginning” that she wanted to be a doctor. She was “always interested in lots of things,” and chose to major in science in college. While obtaining her Masters degree in nutritional biochemistry, she worked at the Hospital for Sick Children in Toronto, Canada. In the late 1980s, as she pursued her graduate studies, a colleague suggested that she might try medical school instead. Her response? “Are you kidding me? I’d never get in!” But she did apply, and she did get in. Then she turned the offer down, because she wasn’t sure she really wanted to go. Dr. Weigel got married, and some time passed, and she began to think: “I may have made a big mistake.”
So Dr. Weigel applied again to medical school, and again she was accepted. She said to her husband, “I probably should do this!” Fortunately, then as now, her husband was wonderfully supportive. And so she went.
Dr. Weigel had loved working with children in the Toronto hospital, but she spent most of her time in medical school trying to convince herself that she would do something else. She was interested in “very intense fields” of medicine and had a strong interest in continuing to do cutting-edge scientific research. After she completed her internship, she realized that she had the most fun during her rotation through pediatrics. So she conducted her residency in pediatrics at the University of Western Ontario. She intended to go into critical care, practicing intensive care medicine.
Then, after a few months in an oncology rotation, “this light bulb turned on.” Dr. Weigel realized that pediatric oncology would allow her to marry her “love of research” with intense medicine, and also would allow her to develop “such incredible relationships with families,” which was something that critical care medicine did not offer.
In this way, an oncologist was born.
Onward, to Minnesota and Sarcoma
Very few options for oncology training were available in Canada, and someone suggested to Dr. Weigel that the University of Minnesota offered what she was seeking. So she and her husband traveled here early one November, when snow already was falling. Contrary to popular belief, Toronto is not quite so freezing as our great state. “The lake effect!”
After her interview here, Dr. Weigel was offered an oncology fellowship with full research funding for three to four years. This research guarantee sealed the deal, and she came in the mid-1990s. Her experience was “really really fantastic.”
Dr. Weigel landed in the lab of Dr. Bruce Blazar, a bone marrow transplant doctor who both worked to control immune system response after transplant and also to develop new ways to use the immune system to treat cancer. Dr. Weigel was drawn to solid tumors and particularly to sarcoma. At that time, the scientific literature was just “this black hole” with respect to sarcomas. Work simply was not being done, in this area “so desperately in need of research.”
So Dr. Weigel expressed her interest, and Dr. Blazar supported her completely. But she needed to blaze her own trail. She could use the lab resources, but she needed to “literally start from scratch” and figure out how to get it done. One has the sense that this challenge itself was a major draw. After weeks combing the literature, Dr. Weigel found a whole series of papers from the East Coast indicating that a cell line had been developed that could be used for research into rhabdomyosarcoma. She contacted Dr. Robert Evans, the retired man behind this work, and obtained his permission to carry on. He was “just incredibly gracious” and sent her the cells, happy to know that someone would use his work. And use his work, she and her University colleagues did.
When asked about what she is doing now, Dr. Weigel said that all her years in basic science research were “a gateway to bring new therapies to children and adults with cancer.” Now, most of her time is spent in early phase clinical trials and translational research, seeking to move new drug therapies out to people.
In talking about the course of her life, Dr. Weigel said she thought it important to “make the most out of whatever opportunity is put in front of you,” and to understand that “you never know what that opportunity will be.” The understanding she has gained through her work with patients and families has been important in shaping her scientific research. We are thankful that Dr. Weigel has poured so much of herself into both research and treatment, fulfilling a dual role she finds it “so crystal clear” must be played.
Hope on the Horizon
After so many years in the dark ages, it is astonishing to learn that sarcomas finally may be emerging into lighter times. Ten years ago, Dr. Weigel wrote a clinical trial design for young people with rhabdomyosarcoma. There were no new drugs available then; just a plan to deliver old drugs in new ways. In the first 18 months after the treatments were delivered, these changes allowed people to live longer overall and extended the length of time that they lived without return of their cancer. Even if the improvements fade away with more time, this is a great accomplishment. And there are promising signs that the benefits will stick.
Today, scientists have the technologies that will allow them to really study tumors in ways they never have been able to study them before. For example, Dr. Weigel and Bridget Charbonneau, a post-doctoral fellow with her colleague Julie Ross, have combed the tumor bank at the University of Minnesota to identify about 180 patients with synovial sarcoma. About 50 of these patients had good tumor tissue available for testing, and the team is looking for genetic markers that might tell them which tumors are more likely to be dangerous. If they can tell which cancers are more deadly, they can give the stronger treatments to those people facing the most danger. And if they can find the bad actors within the cells, they also might be able to develop drugs specially designed to target the cancer.
As science advances, more targeted drugs are becoming available that may hit the sarcoma tumors in ways that could really knock them out. With great folks like Dr. Weigel using this science, we have reason to hope.
When asked for her final thoughts, Dr. Weigel wished to highlight the impact that Rein in Sarcoma have had on the specific research in the field of sarcoma at the University. This, she said, “can’t go unrecognized.” She considers RIS to have been “a huge impetus behind what is now becoming one of the premiere sarcoma programs in the country.” This has been “spearheaded by the Wyckoffs,” and is an “incredible testament” to them and to the whole group of volunteers who have offered their talents and dedication.