This year, we welcome out of state scientist, Berkley Gryder, Ph.D., who serves as principal investigator on the Rein in Sarcoma Kasey Altman Research Fund Grant for alvar rhabdomyosarcoma (ARMS) research at Case Western Reserve University. Initiated in 2021 and titled the Identification of new strategies to therapeutically intervene for rhabdomyosarcomas. Initial funding was $54,000 and included support for twenty-two weeks of a full-time research assistant. Thanks to the success of the 2021 work, an additional $50,000.00 was awarded in early 2022 to peruse in vivo studies based on lead compounds and combinations from the December 2021 proposal.
Dr. Gryder is a chemist who retrained as a molecular biologist and computer scientist. He is passionate about understanding how cancer cells control their genes and developing new chemical strategies to stop cancer cell’s addiction to gene transcription. Along the way, he has proposed paradigm shifts and surprises that are explaining old conundrums. Recognizing that the “right” answer to a tough question is often out of reach with current tools, Dr. Gryder says he is always innovating techniques with an ultra-high level of spatial and temporal precision to study gene control/epigenetics.
Cancers Dr. Gryder’s team aims to cure
In addition to being motivated by the sheer beauty of biology (yes, even when studied in something as ugly as cancer), the research team is also inspired by the tireless efforts of the patients, doctors, family members, and friends that battle cancer. The team believes that the deeper they understand epigenetics and gene control, the better they will be at developing new ammo in the war against cancer. Their lab is currently testing new epigenetic therapies for childhood cancers, especially Rhabdomyosarcoma and lethal forms of Prostate Cancer.
They patent new molecular strategies to cure these cancers and test them in the most disease-relevant models. They also work with teams of medical doctors and chemists across multiple institutions and aim to take their most exciting molecules into the clinic.
Nea Fride is a MSY3 at the University of Minnesota Medical School. She has a BA and BSM from Newcomb College at Tulane University in New Orleans, Louisiana and a MS as a Pathologists’ Assistant from the University of Maryland at Baltimore. Before medical school, she worked in the field of pathology for several years where she commonly saw various soft tissue tumors. She has a passion for molecular pathology and personalized medicine.
Rami Shaker completed his Bachelor’s of Science in Chemistry and Master’s of Health Informatics at the University of Minnesota before starting the MD program. His first experience with oncology research was in his master’s program in a radiomics project under the direction of Dr. Christopher Wilke and he continues to work on other radiomics projects. This experience led to his decision to focus on an oncologic specialty.
Sophia Mavrommatis is originally from Wellesley, MA and graduated from Washington University in St. Louis in 2018 with a Bachelor of Science in Business Administration. She is now a 3rd year medical student at the University of Minnesota Medical School where she serves as Executive President of Student Council and is passionate about pursuing a career in orthopedic surgery.
Mayo Clinic
Lindsay Howlett completed her undergraduate degree in Human Science at Georgetown University, where she participated in cancer-related cell biology research and volunteered as an EMT. These activities instilled in her an appreciation for the science and humanism that work together to best take care of patients. Coming into medical school with an interest in oncology, Lindsay spent her first year at the Mayo Clinic Alix School of Medicine exploring this field through shadowing experiences and tumor board style talks put on by the Oncology Interest Group at Mayo.
Claire Cassianni completed her undergraduate degree at the University of Southern California (USC) in Biological Sciences and went on to earn her M.S. in Stem Cell Research and Regenerative Medicine. Much of the research she was involved within during her undergraduate/graduate studies involved the intersection of oncology, hematology, and regenerative approaches. She also spent immense time with the USC street medicine team caring for those experiencing homelessness who are also struggling with a variety of medical issues, including many forms of cancer. She is now pursuing her M.D. at Mayo Clinic Alix School of Medicine where she is leading the Oncology Interest Group and performing clinical research in both myeloma and oropharyngeal squamous cell carcinoma. As a sarcoma scholar, she is eager to provide mentorship and education. Her interests extend to fostering animals, being outdoors and spending time with her friends and family.
University of Wisconsin
Max Frenkel is a MD/PhD student in UW – Madison’s MSTP. He is passionate about creating genomic tools to make patients’ lives better. His career goal is to use and accelerate scientific revolutions to help make genomic medicine a reality. Max has been interested in the intersection of technology, science, and human health since he was an undergraduate. He received a B.S. from Harvey Mudd College where he spent time in labs spanning computational modeling, organic chemistry, molecular, and structural biology. Max works in Vatsan Raman’s lab where they use new-age genomics techniques to investigate how genetic variation contributes to disease and engineer biological systems to improve diagnosis and treatment. He hopes to eventually contribute to the understanding of complex diseases like sarcomas and help ensure that these advances are rapidly clinically actionable to help patients.
Medical College of Wisconsin
Natalie Stratton became interested in oncology while volunteering on the Onc/Heme Unit at the University of Minnesota Masonic Children’s hospital during undergrad. She loved working with the patients to brighten their days, but ultimately wanted to do something more. Therefore, she began pursuing research in Dr. Branden Moriarity’s lab at the University of Minnesota, where she studied potential targetable oncogenes implicated in osteosarcoma development, as well as some drug development. She has continued shadowing oncology physicians in various sub-specialties. Natalie is involved in multiple research projects, as well as serves as a Co-President for the oncology interest group.
Expanding our understanding of DICERJ-related sarcomas Principal Investigator: Kris Ann Schultz, MD
Project summary: DICERJ-related sarcomas include pleuropulmonary blastoma (PPB), renal sarcoma, ovarian, cervical and uterine sarcoma, renal sarcoma and PPB-like pelitoneal sarcoma which may arise from peritoneal structures. In addition, Sertoli-Leydig cell tumor (SLCT), a rare ovarian tumor seen primarily in girls and young women, may often recur with sarcomatous elements, a clinical situation associated with a poor prognosis. In this proposal, we will leverage our prior Rein in Sarcoma funding and ROI – funded existing PPB-related research activities to include additional data collection regarding specific DICERI -related sarcomas. Development of this additional collated data source is the next step toward our goal of understanding the best treatment regimens for children and adults with DICERl-related sarcomas and sarcomatous recurrence of SLCT.
Multi-Omics to Distinguish Leiomyosarcoma Subtypes Principal Investigator: Brittany Siontis, MD
Project summary: Despite aggressive, multimodality therapy including surgery, radiation, and chemotherapy, more than half of patients will ultimately develop metastatic disease. Research to date has shown the genomic alterations in LMS to be diverse and have been unrevealing of a specific treatment target. The proteome or set of proteins that are or can be expressed by the cancer cells, is thus far largely unstudied. This project proposes an in-depth analysis of the LMS proteome utilizing stored tumor samples representing each of the LMS subtypes. Not only will this work further our understanding of the LMS proteome, but will identify potential pathogenic drivers within LMS as well as differences between subtypes.
Kris Ann P. Schultz, M.D. shares insights into sarcoma research and treatment
Dr. Kris Ann Schultz
Researchers are making progress, with Rein in Sarcoma’s help, in the quest to understand, treat, and prevent sarcoma. Kris Ann P. Schultz, M.D., a pediatric oncologist with Children’s Minnesota, has been involved in both clinical care and research for many years. A recipient of Rein in Sarcoma research grants in 2019 and 2021, Schultz has been working to improve outcomes for children and adults with DICER1-related cancers through early detection and the development of more effective and less toxic therapies.
Rein in Sarcoma recently connected with Schultz to learn more about her work.
RIS: What questions about cancer do you most often get from patients and families?
Schultz: Patients and families often ask how they can help. It’s inspiring to me that so many families, in the midst of their challenging journeys, also consider how they can contribute to research to help others.
One suggestion is to work with your medical care team early on and ask at the start, throughout and at the end of treatment, if there are any studies you should know about or that you could consider joining. Talk with your doctor and research team.
When families first think about cancer research, they often think about clinical trials, where the treatment that someone receives is based on a study protocol. Those are really important studies that may offer access to novel therapies, so it is important to discuss these with your health care team as you consider whether this type of study is right for you. There are also other forms of clinical research in addition to clinical trials. You can participate by sharing tumor tissue or blood samples or sharing clinical information in a registry or a natural history study. Tissue-based research allows scientists to study how particular cancers may be vulnerable to new treatments and registry and natural history studies are valuable as well, especially in rare cancers as researchers can use these databases to track outcomes over time and look for patterns.
RIS: How does genetic testing help the patient?
Schultz: Genetic testing, broadly, can mean two different things, testing the person and/or testing the tumor. Testing the person, usually though blood or saliva testing, is also called “germline” testing and this can help individuals and doctors understand why a tumor developed and whether the individual or family members have any increased risk for tumor development.
Knowing your family history can make a difference when it comes to advocating for yourself and your loved ones.
In our DICER1 research, we have seen the tremendous impact of this kind of genetic testing. DICER1-related tumors may be hereditary. Knowing your family history can make a difference when it comes to advocating for yourself and your loved ones. Our motto here is ‘knowledge is power’ — which clearly applies to DICER1 related cancers and many other forms of cancer as well.
It is also now possible to test the tumor itself, to look for changes in the tumor cells, generally not found in the person, that may help to guide treatment options. We’re at averyexciting time in oncology where this kind of germline and tumor testing can inform surveillance for early detection and novel treatment options, but we still need lots more research to determine how best to implement all of this.
RIS: What are the main areas of focus in your current research?
Schultz: We’re trying to optimize treatment for all DICER1-related cancers both using strategies available now and also considering potential strategies in development. We also want to understand how best to detect tumors in their earliest and most curable form and trying to develop better ways to measure tumor response to treatment.
This is an exciting time for research. Researchers in general are learning how to harness the patient’s immune system and the unique changes within tumors and we’d like to better understand how this applies to pediatric cancers. This is a broad effort by many people, but each breakthrough contributes to what we know and can advance clinical care.
RIS: How did the COVID-19 pandemic affect your research, and sarcoma research in general? Did research slow down?
Schultz: During the pandemic lockdowns, there were limits on the number of people who could work in labs but on the bright side, the emerging use of web conferencing made it easier to connect globally with other researchers.
There is a broad base of international participation in sarcoma research. Web conferencing has really advanced our internationally collaborative efforts and brought researchers together globally.
RIS: How did you get involved in research?
Schultz: My road to research really started with clinical care. As a pediatric oncologist, I care for kids with cancer and blood disorders. There is no better motivation than these kids and their amazing families to drive advances in care. Plus, kids (and their parents) ask the best questions which really spurs research forward. The clinical side really informs the research, and the research informs clinical care — the best synergy!
RIS:What do you most want people to understand?
Schultz: Everyone’s efforts make a difference. Each part helps, whether it’s sharing your genetic or clinical data with a registry, participating in a study, or getting involved through philanthropy.
I like the phrase: Learn, connect, consider.
Learn about sarcoma cancer and your family history. Connect with a support network, medical care and researchers. Consider how you can get involved.
In particular, we’ve found that the samples collected early in a cancer journey are so critical to research. Iin those early stages, there’s so much yet to be determined and so it can be challenging to get those samples into the hands of researchers who are working on those topics.
The earlier the conversation begins, the more likely it is that critical data will be captured and routed to researchers who can work toward answering the next big research question. Now that awareness of sarcoma cancer has grown, it is my hope that we’ll be able to create those connections earlier as each tumor is discovered and treated.
RIS: Thank you for sharing your time with us today. As an oncologist and researcher, you bring hope to many. Rein in Sarcoma is honored to support your work.
___
Kris Ann P. Schultz, MD, is a pediatric oncologist and Pine Tree Endowed Chair in Cancer and Blood Disorders Research and also serves as Scientific Director of Cancer and Blood Disorders at Children’s Minnesota. Dr. Schultz is the Principal Investigator for the International
Pleuropulmonary Blastoma (PPB)/DICER1 Registry and the Principal Investigator and founder of the International Ovarian and Testicular Stromal Tumor (OTST) Registry. Her current research focuses on improving outcomes for DICER1-related tumors. Dr. Schultz joined the Hematology Oncology program at Children’s Minnesota in 2008 and has particular interest and expertise in the care of children with pleuropulmonary blastoma, ovarian tumors and other rare childhood cancers.
Rein in Sarcoma and research
A major component of Rein in Sarcoma’s mission is to fund research directed toward developing new treatments and finding cures for sarcoma cancers. Since our inception in 2001 RIS has funded nearly $2 million to sarcoma research projects, primarily at the University of Minnesota, with an expansion to the Mayo Clinic and Children’s Minnesota in 2017. These research dollars in turn have resulted in additional grants totaling over $13 million in public and private funding to date.
For more information on Dr. Schultz’s Rein in Sarcoma research grant projects see:
On March 25, 2022, the Rein in Sarcoma community hosted the annual Research Symposium where 2019 and 2020 grant-winners showcased their research.
The gathering was held in a hybrid format where viewers could watch the speeches online if they weren’t unable to attend in person. A total of 29 viewers from across the country tuned in to listen, while an additional 38 viewed in person.
The presentations ranged across diverse topics in medicine, yet most importantly contained their own applicability to sarcoma. Presenters included:
Dr. Brenda Weigel, Dr. Kris Ann Schultz: DICER1 Related Genitourinary Sarcomas
Ashley Schulte: eBAT as a Modulator of the Myeloid Immune Checkpoint in Cancer
Dr. Logan Spector: Medication-Associated Phthalate Exposure and Childhood Cancer Incidence
Dr. Fabrice Lucien: Integrated Proteomic and Transcriptomic Profiling of Rhabdomyosarcoma Reveals Target Antigens for Immune-Based Therapies and Targeting the Immune Checkpoint B7-H3 for the Treatment of Rhabdomyosarcoma
Dr. David Largaespada: SHH signaling genetic alterations: A relevant and targetable trait in peripheral nerve sheath sarcomas,
Dr. Ruping Sun: Computationally Deciphering the Paths of Genomic Catastrophe in Osteosarcoma
Dr. Masato Yamamoto: MYOG:Promoter-Controlled Oncolytic Adenovirus to Treat PAX3-FOXO1-Positive Rhabdomyosarcoma.
The day also highlighted the RIS Jan Maudlin Sarcoma Scholar program promoting sarcoma awareness through peer education. Past Maudlin Scholars – Kristine Nachbor, Guy Guenther and Tori Bar, along with current scholar, Alex Nelson, met and discussed with the researchers as well as with Tim and Jan Maudlin. The Maudlins have sponsored the scholarship program for over 10 years. The 56 program alumni help support sarcoma education and awareness thanks to the generosity and vision of Jan and Tim Maudlin!
The next annual symposium will be held in March 2023 to highlight the 2021 grant-winners’ research. Further details on the event date and location will be communicated as the date approaches.
Rein in Sarcoma’s Board approved a $50,000 research grant to the University of Minnesota at its February, 2022 meeting.
The University solicited requests for funding proposals from their researchers, blindly ranking them according to national standards, and then recommended the proposal submitted byDr. Beau Webber, PhD.
Ewing sarcoma (EWS) is the second most common pediatric bone sarcoma cancer and accounts for ~2% of all pediatric cancers. Survival, which is as low as 70%, has not improved in decades despite the discovery in 1983 of the pathognomic fusion oncoprotein, EWS-FLI1. EWS is unusually homogenous in its tumor biology, with~90% featuring EWS-FLI1. Despite extensive knowledge of EWS-FLI1, it has proven difficult to target directly, thus attention has turned towards its interaction with the genome and downstream transcriptional and epigenetic consequences. We have developed an induced pluripotent stem cell (iPSC) system for examining genomic interactions and downstream consequences of EWS-FLI1 expression; to date we have only implemented this system in unaffected control iPSC. We have successfully created 3 patient-derived iPSC from viably frozen blood samples; 2 more iPSC created by colleagues at the University of Utah are currently being added to the bank. Banked patient-derived iPSC will be made available to the Ewing sarcoma research community but will be more valuable with certain data available. This project seeks to more fully characterize the iPSC we have banked to date. New long-read sequencing technology, such as by PacBio and Oxford Nanopore (ONT), makes it possible to create genomes that accurately capture GGAA repeats and other structural variation which has previously been obscure. Only recently has the output and price of these experiments become tractable for individual labs. We now propose a series of assays of our EWS patient-derived iPSC that will both serve to enhance future applications using these lines and answer several substantive questions in themselves.
