Dr. Chandler’s research is centered on understanding the regulation of alternative pre-mRNA splicing and how disruption of this highly regulated process leads to pediatric diseases such as cancer. Her research focus is to define the mechanisms by which disruption of regulated splicing of pre-mRNA leads to altered cell function. Dr. Chandler’s lab is developing in vitro and animal model systems that can be used to develop novel therapies targeting these disrupted pathways. Dr. Chandler received a B.S. in Microbiology/Chemistry from Texas A&M University and a Ph.D. in Genes and Development from the University of Texas’ Graduate School of Biomedical Sciences in Houston, Texas. She conducted post-doctoral research in human genetics and in cancer genetics at the University of Texas M.D. Anderson Cancer Center. Dr. Chandler is currently faculty in the Department of Pediatrics at The Ohio State University College of Medicine and the Center for Childhood Cancer at Nationwide Children’s Hospital. Dawn is a member of the Ohio State University Comprehensive Cancer Center and American Association for Cancer Research. She is also a teacher and mentor for the Biomedical Sciences Graduate Program and Co-Director of the Molecular, Cellular and Developmental Biology Graduate Program at the Ohio State University.
Osteosarcoma is the most common pediatric primary bone malignancy. Fortunately, through modern medical advances most children with localized tumors can be cured. However, children with metastatic disease at the time of diagnosis or who relapse after treatment have a poor prognosis and survival rate. The molecular events that distinguish these tumors are poorly understood. Compounding the roadblocks to new therapy development is the lack of understanding of the mechanisms that contribute to treatment resistance of these tumors. The Chandler Lab is trying to understand the way in which tumors become metastatic and resistant to drug treatment, so that we can interfere to kill the tumor. Rapid growth of the tumor caused by increased cell number creates an environment of low oxygen levels, a condition called hypoxia. Normal cells cannot survive hypoxic conditions. However, tumor cells are able to adapt and thrive in low oxygen levels. The Chandler Lab has shown that low oxygen levels induce expression of the insulin receptor A gene (IN R-A) as an essential step for tumor growth and metastatic disease. Interestingly, IN R-A is generated by a process called alternative splicing by which sections of the gene can be differentially included or excluded. This IN R-A “isoform” consequently has increased binding affinity for growth factors, which the tumor secretes to promote its own growth. The proposed work in the Chandler Lab will interfere with alternative splicing of the IN-R gene so that the important region is once again included to generate the native IN-R isoform to facilitate normal cell growth and metabolism.
Dr. Joanna Kitlinska, Associate Professor at the Department of Biochemistry and Molecular & Cellular Biology, Georgetown University Medical Center
"One of the most difficult obstacles in treating malignant tumors is their ability to change, allowing them to adapt to growth in different metastatic sites and overcome therapy. Using our metastatic model, we have found that Ewing sarcoma dissemination is preceded by formation of atypical, large tumor cells with increased number of chromosomes, so called “polyploid cells”. Such cells are known to give rise to genetically instable, highly adaptive progeny. Thus, we hypothesize that these atypical Ewing sarcoma cells initiate metastases and perhaps also resistance to therapy. Our study will directly test this hypothesis. If successful, our research will provide a foundation for further studies designed to determine if targeting such atypical tumor cells will hinder the ability of the Ewing sarcoma tumors to evolve and prevent their progression into a metastatic, chemoresistant phenotype. Importantly, this phenomenon may also apply to other pediatric tumors, such as neuroblastoma, since polyploid cells have been implicated as an origin of the aggressive form of this disease." -Dr Kitlinska
Marcela Briones, PhD, UCSF
Marcela Briones is a postdoctoral scholar at the laboratory of Dr. Alejandro Sweet-Cordero at the University of California, San Francisco. She received her Ph.D. degree in Molecular Biology at the Institute for Scientific and Technological Research of San Luis Potosi, (IPICYT), a federally funded research institute in central Mexico. During her Ph.D., she worked with the opportunistic human fungal pathogen Candida glabrata. Marcela has published her work in high-quality peer-reviewed journals in various areas such as yeast Genetics and Molecular Microbiology. Currently, she has around 125 citations.
She is enthusiastic about working on novel challenging projects, and now she is interested in understand the transcription regulation mechanisms that drive the Ewing’s sarcoma in the laboratory of Dr. Sweet-Cordero.
The Ewing’s sarcoma is an aggressive and devastating bone cancer in children and adolescents. The standard treatment consists of local radiation, legs/arms amputations and chemotherapy. Despite this multimodal treatment, very often metastasis appears in these young patients leaving them with only a 20% chance of surviving and poor quality of life. Thus, Ewing’s Sarcoma biology research is required for the development of new therapeutic approaches.
The Sweet-Cordero laboratory has discovered the presence of a specific long RNA molecule called EWSAT1 in Ewing’s cells, which has an important role in the maintenance of the tumors. The main goal of Marcela is to determine the precise mechanism of action of EWSAT1 and how it interacts with other important molecules to drive uncontrolled growing in Ewing’s cells. To know the specific role of EWSAT1, she will repress this molecule to avoid its presence in Ewing’s cells using the innovative CRISPRi technology. Then, she will analyze the consequence of its loss by determining changes in the molecular behavior of these cells. Dr. Sweet-Cordero and her think that this research will give us new clues on how to fight against these malignant cells.
Siu Ping Ngok, Post-doctoral Fellow, Stanford University
Due to Sunbeam’s support, Dr. Sweet-Cordero’s Lab (with vital contributions from his fellow, Ngok), successfully discovered a mouse model to express EWS-FLI-1, thus mimicking what happens in human patients. However, they have been stymied by the fact that they have not found a way to express this translocation only in the right cell type--if it is expressed in the wrong tissues, it kills the mice. Sweet-Cordero and Ngok believe they have solved this problem and have found the right cell type thanks to related work published by other groups. They are now poised to make the updated, final model, but it is expensive. Once they get the model, the lab is confident they can get additional funding to pay for broader work, but without a model in hand, this is practically impossible. Sunbeam has awarded Sweet-Cordero with the Sunbeam Grant and Ngok with the Sunbeam Scholar Grant to help them in their quest to complete this crucial step toward our bigger goal.
"Pediatric sarcomas are among the most aggressive cancers that strike children and teens. The most important factor influencing the survival of children with sarcomas is metastasis—the spread of cancer to other parts of the body. A child diagnosed with a sarcoma has a 70-80% chance of cure, provided they have not developed metastasis. If the tumor has spread, however, that same child will have a 70-80% chance of dying, even with aggressive therapy. Despite the importance of metastasis to outcomes in these cancers, we understand very little about why or how they spread.
Our research has identified changes within the cells of childhood sarcoma—osteosarcoma—that drive aggressive behaviors associated with metastasis. We have found that these tumor cells can change the way they express a group of genes from the p53 gene family. The alternatively expressed forms of these genes, called ΔN (“delta-N”) isoforms, activate pathways within the tumor cells that make them behave aggressively.
Our research suggests that targeting activated pathways (for example, IL6/8 and STAT3) could suppress the aggressive behaviors that ΔN isoform cause. This may interrupt critical steps in the metastatic process and prevent metastases from forming. With this grant, we will test whether drugs that block deregulated pathways caused by ΔN isoform can prevent metastasis and enhance survival. These strategies could translate directly into treatments that would save lives by preventing metastasis in children with pediatric sarcomas."
(Special Donor Award, additional grant initiated thanks to a generous donation)
"The major goal of our lab is to understand the earliest steps in cancer at a molecular level. Our focus is on defining novel cancer genes and on understanding the developmental biology of tumors. To accomplish this, we have turned to the zebrafish system. The zebrafish is a wonderful complement to mouse, fly, worm, and other disease models. The fish produce large numbers of progeny weekly and are easily maintained, allowing us to take large-scale, genome-wide approaches. The transparent embryos develop external to the mother and are accessible to manipulation with transgenic or antisense approaches. At the same time, fish have true vertebrate anatomy and physiology, and are susceptible to the same tumors as are humans, making them an excellent cancer model."
Siu Ping Ngok, Postdoctoral Research Fellow, Pediatrics Cancer Biology, Stanford University
"My interest in cancer research was developed through my undergraduate research experiences, where I studied oncogenic metabolic mutations at the Penn State Medical Center and partook in a genetics research project led by the Broad Institute during my senior year in college. Fueled by these fulfilling experiences, I began my PhD studies in the Pharmacology & Therapeutics program at the Mayo Clinic. In my PhD work I focused on translational research and the study of novel molecules that may have implications in tumorigenesis and metastasis. It was through my graduate work that I realized pediatric sarcomas are “orphan diseases” that, historically, have received little attention. Yet these malignancies cause significant morbidity and mortality in children and adolescents, and bring about significant grief and burden to patients and their families. As someone who enjoys both biomedical research and working with children and adolescents (throughout my graduate school, I volunteered at numerous community events where the targeted audience ranged from young children to high school students), I was inspired to become an independent, cancer research investigator in the field of pediatrics. Dr. Sweet-Cordero’s laboratory has a main focus in studying and identifying targeted therapeutic approaches for pediatric sarcomas, and joining his group was a natural move for me upon the completion of my Ph.D.
I am committed to identifying key genetic events for the onset of Ewing’s sarcoma and deconstructing the oncogenic properties of long non-coding RNAs, with the ultimate goal of developing novel therapeutic approaches for treatment. I intend to publish findings that are made possible by the generous support from the Sunbeam Foundation. Subsequently I will apply for the NIH K99/R00 Pathway to Independence Award, which will provide me the funding to continue my work in pediatrics cancer as an independent researcher after my 3-4 year fellowship in Dr. Sweet-Cordero’s laboratory."
Dr. Michael Engel is a physician-scientist and pediatric hematology/oncology physician at Primary Children’s Medical Center and the University of Utah School of Medicine, and is an investigator in Oncological Sciences at the Huntsman Cancer Institute-Center for Children’s Cancer Research.
Ewing sarcoma is characterized by a t(11;22) chromosomal translocation creating a hybrid gene that encodes the EWS/FLI translocation fusion protein. EWS/FLI alters the expression of target genes to promote the transformed phenotype in Ewing sarcoma. Among these genes is NKX2.2, which is required for EWS/FLI-mediated transformation. The NKX2.2 protein has both transcriptional repressor and activator functionality, but it is the repressor function of NKX2.2 that is required to maintain the transformed phenotype in Ewing sarcoma. In contrast, the transactivation function of NKX2.2 reverses the transformed phenotype, suggesting that its transactivating functions must be suppressed to allow the transformed phenotype to be established and maintained. We and others have shown that activation of the Notch signaling cascade suppresses growth and transformation in Ewing sarcoma cell lines. In parallel, we have found that the NKX2.2 domain responsible for transactivation, TAD, binds the transcriptional co-repressor MTG16, and that Notch signaling disrupts this interaction. We hypothesize that MTG16 suppresses transactivation by the NKX2.2 TAD to permit survival of Ewing sarcoma cells, and that Notch activation disrupts the MTG16—NKX2.2 interaction to expose growth inhibitory and anti-clonogenic properties of the TAD. As such, the NKX2.2—MTG16 relationship may be an “Achilles heel” in Ewing sarcoma, and signals transmitted by Notch could unlock this weakness. Using differential RNAi approaches, we are testing this hypothesis, and in so doing working toward strategies that might allow us to exploit these relationship for therapeutic benefit.
Sunbeam Scholar 2013, 2012
Bethsaida was born and raised in Brooklyn, NY and then moved with her family to Teaneck, NJ, a small town just outside of Manhattan. She did her undergraduate studies at Pennsylvania State University in State College, PA where she not only became a huge football fan, but also developed a passion for research. During that time, she joined Dr. Craig Cameron's lab in the Biochemistry department and later received her B.S. in Genetics and Development Biology. From one cold state to another, she enrolled in the graduate studies program at Albany Medical College in Albany, NY, where she worked under the mentorship of Dr. Susan LaFlamme. After receiving her PhD, she relocated to sunny California and joined the Sweet-Cordero lab as a postdoctoral fellow where she is currently studying Ewing's sarcoma, a rare bone and soft tissue cancer found in children and adolescents. Her research is focused on analyzing the consequence of EWS/FLI-1 expression in human mesenchymal stem cells in vitro and in vivo as well as identifying mechanisms responsible for resistance to chemotherapy in Ewing's sarcoma.
Dr. Kimberly Stegmaier is a physician-scientist and pediatric oncologist committed to finding new treatments for childhood cancers. She is an Associate Professor of Pediatrics at Harvard Medical School and an Independent Investigator at Dana-Farber Cancer Institute. She is also an Associate Member of the Broad Institute of Harvard and Massachusetts Institute of Technology and an Attending Physician at Dana-Farber Cancer Institute and Boston Children’s Hospital. Dr. Stegmaier received her undergraduate degree from Duke University, medical degree from Harvard Medical School, and trained in Pediatrics and Pediatric Hematology/Oncology at Boston Children’s Hospital and Dana-Farber Cancer Institute. In 2006, she launched her own laboratory at DFCI. She is the 2012 recipient of the Young Investigator Award from the Society for Pediatric Research and the 2013 recipient of the Sir William Osler Young Investigator Award. Dr. Stegmaier’s research program seeks to discover new cancer targets and drug leads by integrating chemical biology, functional genomics, next-generation sequencing and proteomic approaches, with the mission of translating laboratory findings to the clinic. One focus of her laboratory is on childhood cancers driven by cancer-promoting proteins that have been difficult to target with standard approaches to drug discovery. One such disease, Ewing sarcoma, is the second most common childhood cancer involving bone. Her laboratory has developed new approaches using gene expression signatures to discover drugs which target the cancer promoting protein called EWS/FLI in Ewing sarcoma. A second approach used by her laboratory is the systematic “knockdown” of each gene in Ewing sarcoma cells to identify genes whose depletion kills Ewing sarcoma cells. It is her hope that these “vulnerability” genes will further scientific understanding of this cancer as well as lead to the development of new drugs to treat patients suffering from Ewing sarcoma.
Despite aggressive local control measures and systemic chemotherapy, over a quarter of patients with localized Ewing sarcoma family tumors (EFT) and nearly all patients with metastatic disease will relapse at distant sites following a period of initial clinical remission. Unfortunately, the outlook for these patients is dismal and novel approaches to therapy are desperately needed. One of the biggest impediments to improving outcomes and quality of life for patients with EFT is our inability to effectively identify and target the cells that initiate tumor metastasis. The studies outlined in this proposal aim to address these critical gaps in our knowledge.
In other tumors it has been shown that a protein called CXCR4, which is present on the surface of some tumor cells, responds to circulating factors and induces the tumor cell to invade surrounding tissues and travel to distant sites. Preliminary evidence from our lab and others suggests that some EFT cells express high levels of CXCR4 and that these cells may be the cells that initiate metastasis. Importantly, a new class of compounds that inhibits a key biologic pathway that is activated by CXCR4, the Rho-MKL pathway, has recently been described. In laboratory models these compounds have been shown to inhibit the invasion of other aggressive tumor types including melanoma and prostate cancer and early studies in our lab indicate that they may also be effective at inhibiting EFT cell invasion. In this proposal we will test the hypothesis that CXCR4 positive tumor cells and the Rho-MKL pathway are key mediators of EFT metastasis. In addition, we will test small molecule inhibitors of the RhoA-MKL pathway to evaluate their efficacy as potential novel agents for the prevention of EFT metastasis. It is our long-term goal, through these studies and others, to improve outcomes for patients with EFT by preventing metastatic relapse.
For over 30 years natural killer cells (NK cells), one of the white blood cells of our immune system, have been known to kill many types of cancer cells, including those that occur in children such as AML, neuroblastoma, osteosarcoma, and Ewing's sarcoma. Different than T cells and B cells, which are trained to recognize special tumor-specific targets, NK cells require no special training. Under the right circumstances, cells in the body raise the alert level for NK cells, allowing them to recognize tumor cells or virus-infected cells on the basis of "danger" signals. Many new therapies, such as antibodies or immune modulating agents, work by increasing the danger signals recognized by NK cells, and therefore require NK cells in order to be effective. However, cancer often makes NK cells dysfunctional, and these cells are further damaged by chemotherapy. Recent studies have shown that healthy, functional NK cells can be safely transferred from a normal donor to a patient, but this approach is limited by the low numbers of NK cells that can be extracted from a donor, the cost of collecting NK cells, the cost and side effects of certain drugs (cytokines) needed to improve NK cell function, and the ability of cancers to escape being recognized by NK cells.
We recently developed a method to grow NK cells in the lab (increasing the numbers by 30,000-fold or more in 3 weeks), so that a small amount of blood from a donor can produce enough cells to deliver repeated large doses of NK cells in clinical trials. This system also dramatically raises the NK cell "alert level" to tumor targets. Our current project funded by the Sunbeam Foundation is to see whether we can grow large numbers of functional NK cells from patients with bone sarcomas, and to identify optimal immune modulating drugs that will make bone sarcomas express their "danger" signals so that they are even more likely to be killed by NK cells. We are working to combine these two approaches in first-in-human clinical trials with the hope of developing an effective, low-toxicity, immune therapy for bone cancers.
Dr. Scott C. Borinstein is the newest exciting addition to the Sunbeam team. He is an Assistant Professor in the Department of Pediatrics Division of Pediatric Hematology/Oncology at Vanderbuilt University. Dr Borinstein received his bachelor's degree from the University of Richmond followed by his MD and PhD from Medical College of Virginia at Virginia Commonwealth University. At Seattle Children's Hospital, University of Washington, Dr. Borninstein conducted is residency program. From 2005-2008, he did a Fellowship in Pediatric Hematology/Oncology at Seattle Children's Hospital at the University of Washington, Fred Hutchinson Cancer Research Center in Seattle Washington. In 2009 Dr. Bornstien became an assistant Professor, in the Department of Pediatrics, Division of Pediatric Hematology/Oncology, at Vanderbilt University where he is also the Director of the Pediatric Sarcoma Program. Dr. Bornstiens prolific young career and exciting and promising research is a wonderful addition to our family.
Dr. Borinstein's research focuses on the development of better treatment for pediatric sarcomas. Specifically, his laboratory investigates how changes in DNA methylation contribute to the pathogenesis of Ewing Sarcoma. DNA methylation is an epigenetic mechanism that contributes to the regulation of genes. His laboratory is trying to understand how DNA methylation contributes to Ewing Sarcoma tumor formation and spread and to determine if methylation of certain genes could play a role in diagnosis, treatment, or the development of novel treatments for this disease. The Sunbeam Foundation is extremely excited about Dr. Borinstein's research and we are proud to support him.
Dr. Lessnick is an Assistant Professor of pediatrics, adjunct Assistant Professor of oncological sciences, and an investigator at the HCI Center for Children. Lessnick earned his bachelor's degree from Brandeis University followed by MD and PhD degrees from the University of California, Los Angeles (UCLA) as part of the Medical Scientist Training Program (MSTP). He conducted his internship and residency at Children's Hospital in Boston, followed by a fellowship in pediatrics hematology. He completed postdoctoral research in the Pediatric Oncology Department at the Dana-Farber Cancer Institute and joined HCI in January 2004.
Dr. Lessnick's Lab is interested in determining what genes are regulated by EWS/FLI (the key tumor-causing molecule in Ewing's Sarcoma), the role these genes play in the formation of Ewing's Sarcoma, and any other genetic alterations required for the genesis of Ewing's Sarcoma. To study these factors, Dr. Lessnick has developed model systems that allow the EWS/FLI to be turned on and off at will to determine which targets are altered and their roles in the development of Ewing's Sarcoma tumors. Through this process, Dr. Lessnick hopes to develop a complete understanding of the molecular basis of Ewing's Sarcoma and to apply this understanding to the treatment of patients with this devastating disease.
Dr. Alejandro Sweet-Cordero is paving the way to find better treatments for Ewing’s sarcoma, the second most common type of bone cancer in children. After completing medical school and residency training at the University of California, San Francisco, Dr. Sweet-Cordero became a post-doctorate fellow at the Broad Institute and Massachusetts Institute of Technology Center for Cancer Research and Dana-Farber Cancer Institute. It is here that he conducted his initial studies on Ewing’s sarcoma. He is now continuing this work in his own independent laboratory at Stanford.
Dr. Sweet-Cordero’s laboratory is attempting to reproduce, in a mouse, the genetic abnormality seen in patients with Ewing’s sarcoma. By using genetic engineering techniques, they are developing mice with the abnormal chromosome translocation that is seen in children with the disease. The goal is to study how Ewing’s sarcoma develops in a living organism. For example, it is not known what type of cell in the body is the cell of origin for Ewing’s sarcoma. By activating the translocation in different tissues within the mouse, and observing which mice develop cancer, Dr. Sweet-Cordero hopes to be able to answer this question. Generating mice that have a Ewing’s sarcoma-like cancer will also allow him to test novel therapies for use in humans.