Alexandra Miller, MD, PhD

Funded by the Dick Vitale Pediatric Cancer Research Fund

Primary brain tumors are the most common solid tumors in children. They are also the most frequent cause of cancer-related death in children and teens. Genetic profiling is an important tool in the treatment of these tumors. DNA sequencing provides information for proper diagnosis. It can also be used to understand how tumors change over time and to monitor response to treatment. However, performing biopsies is very challenging for brain tumors.  Many tumors are in important areas of the brain and can’t be fully removed or repeatedly sampled.

“Liquid biopsy” is a new tool that can be used to diagnose cancer and track response for some systemic tumors. It works by detecting small pieces of DNA that break off from tumors. These can be found in the cerebrospinal fluid (CSF) and in blood (circulating tumor DNA, ctDNA). Accessing these “liquids” is usually easier and has fewer complications than surgery.

We previously showed that CSF ctDNA can be used to diagnose brain tumors and that ctDNA is associated with active disease. But there are instances where CSF ctDNA is not informative due to technical limitations. We propose to improve how these samples are analyzed so CSF liquid biopsies can help more patients. Our prior work was retrospective. For this project, CSF ctDNA monitoring will be added to a clinical trial. We will investigate whether there is a relationship between CSF ctDNA and disease burden. Validating CSF liquid biopsy could greatly improve how pediatric primary brain tumors are diagnosed and treated.

Christopher R. Vakoc, MD, PhD

Co-funded by the Dick Vitale Pediatric Cancer Research Fund and the Jeff Gordon Children’s Foundation

What big question(s) will your work answer? Rhabdomyosarcoma is a deadly cancer that occurs in children and young adults. Several decades of research points to a specific molecule (called PAX3-FOXO1) as the most compelling drug target in this disease. However, we simply do not understand the molecular details of PAX3-FOXO1 enough to made a medicine that exploits this target. The big question addressed in this project will be to understand this compelling target with atomic detail by applying innovative technology. • Why does this question matter? Children continue to die of rhabdomyosarcoma and yet the medicines used in the clinic are woefully inadequate and toxic. A new therapy tailor-made for this disease could change everything. • How will your work answer the big question? Our work has the potential to provide a basic science foundation upon which a drug discovery campaign could be launched.

Chia-Wei Cheng, PhD

In the past decade, the incidence of pediatric IBD has doubled, and that of early-onset CRC has quadrupled in the United States. The aggressive clinical course of IBD and reduced overall survival of associated young-onset CRC represent an unmet clinical need. Notably, although the reasons for the upward trend of childhood IBD and early-onset CRC are poorly understood, food and nutrition that raises blood sugar have been identified as the major risk factor. Our research takes the nutrigenomic approach to investigate food-gene regulatory networks that can be exploited for harnessing tumor-initiating cells and pro-tumor inflammation. We anticipate that new mechanistic links and therapeutic targets identified in this study will inspire novel preventive and curative strategies to combat inflammatory diseases and cancer.

Santosha Vardhana, MD, PhD

The role of the immune system is to survey the body in search of dangerous “non-self” elements and to eliminate them without damaging the host. Cancer is a disease which develops when host cells genetically change and begin growing in an uncontained fashion. It was therefore thought for many years that the immune system was incapable of recognizing or eliminating cancer cells due to their emergence from, and similarity to, “self” elements. The remarkable discovery that blocking signals (“immune checkpoints”) that restrain the ability of immune cells to recognize and destroy foreign elements can enable the immune system to treat cancer has fundamentally changed our approach to the treatment of these patients. Even in the setting of immune checkpoint inhibitors, however, immune cells lose functionality within tumors as part of a stepwise process known collectively as T-cell “exhaustion.” Reversing T-cell exhaustion is essential to make immunotherapy a viable treatment for all patients.

Our laboratory recently discovered that the metabolism of T-cells – the way that cells take up, break down, and utilize nutrients – becomes dysfunctional within tumors and, and moreover that this metabolic switch is required for T-cells to become fully exhausted. In work supported by the V foundation, we will understand how tumors exploit this metabolic dysfunction by creating metabolically inhospitable environments in which T-cells lose their capacity to control tumor growth. By identifying and reversing these environmental barriers, we hope to reverse or prevent T-cell exhaustion and make immunotherapy a viable strategy for every patient.

Chrysothemis Brown, MD, PhD

Funded by the Dick Vitale Pediatric Cancer Research Fund

Within days of birth, trillions of harmless, and even beneficial, bacteria colonize an infant’s skin and gut. The developing immune system must learn to tolerate these “commensal” bacteria to avoid the onset of destructive inflammatory diseases such as eczema and inflammatory bowel disease. Remarkably little is known about the cell types that instruct immune cells to accept commensal bacteria in early life. Our research will address the cross-talk between microbes and the developing immune system to elucidate the mechanisms by which the host and bacteria learn to develop a harmonious, symbiotic relationship. In this effort, we seek to reveal the role of a newly identified, early-life immune cell in establishing acceptance of commensal skin microbes. Overall, the project is expected to provide insights into basic mechanisms of immune-regulation, clues to pediatric inflammatory diseases, and a path to the development of new therapies.

Christopher Park, MD, PhD

Funded by the Dick Vitale Pediatric Cancer Research Fund

Acute myeloid leukemia (AML) in children is difficult to treat, and thus it is important to identify new and less toxic therapies.  We have identified a protein called CD97 that is present on AML cells and is required for their maintenance. Because CD97 is present in multiple forms, we will determine which are required in AML cells. We also will make and test the ability of antibodies we have made against CD97 to eliminate AML cells.  We expect our studies will not only reveal the role of CD97 in the development of childhood AML, but identify a potential new drug that may be used to treat kids with AML. 

David Loeb, MD, PhD

Funded by the Dick Vitale Pediatric Cancer Research Fund

Ewing sarcoma is the second most common bone tumor in children, adolescents, and young adults.  Patients who are diagnosed with a tumor that has not spread are usually cured.  Those who are diagnosed with metastases (the tumor has spread from its initial location) are rarely cured despite decades of clinical trials and intensifying treatment regimens aimed at improving their survival.  In preliminary animal experiments, we found that a drug called DFMO, already approved by the FDA for the treatment of African Sleeping Sickness, can inhibit Ewing sarcoma metastasis.  We will test the hypothesis that DFMO acts by interfering with critical metabolic pathways in tumor cells, that it is safe to combine DFMO with chemotherapy, and that the combination of DFMO and chemotherapy will work better than chemotherapy alone in prolonging the lives of mice with Ewing sarcoma.  Assuming we can show that the combination of DFMO and chemotherapy is better than chemotherapy alone in our mouse model, this will provide the rationale for future clinical trials testing the effectiveness of adding DFMO to standard chemotherapy regimens for Ewing sarcoma patients. 

Alison Taylor, PhD

Funded by the Constellation Gold Network Distributors

Genetic information is carried in DNA, which is present in every cell of our bodies. Most cells have 46 chromosomes, which carry DNA within the cell. However, more than 90% of tumors have cells without the correct number of chromosomes. These cells are called “aneuploid”. Some whole chromosomes or large chromosome fragments may be duplicated or lost. Aneuploidy is a contributing factor in cancer formation. However, its exact role in this process is an unanswered question in cancer biology. The goal of this research is to understand the effects of different changes in chromosome number.  

For our studies, we make use of a new technology that allows us to cut chromosomes at specific locations. With these experiments, we can study the effects of changes in large chromosome segments. Our current focus is a type of cancer called squamous cell carcinoma (SCC). In this cancer type, large pieces of chromosome 3 are affected. Here, we will uncover the interaction between chromosome 3 changes and DNA mutations. We will also create a human cell model of SCC. These studies address a gap in our understanding of aneuploidy in cancer by studying the effects of specific sets of chromosomal changes. With knowledge of how these chromosomal changes contribute to cancer formation, we will uncover new ways that cells can become cancerous. A better understanding of paths to disease formation will be crucial for designing new cancer treatments. 

Margaret Callahan, MD, PhD

Funded by the Stuart Scott Memorial Cancer Research Fund in memory of James Ebron *

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Immune checkpoint blockade (ICB) is one type of immunotherapy that has been FDA-approved for the treatment of melanoma, bladder cancer, lung cancer, and other cancers. For some patients, ICB can lead to dramatic shrinkage of their tumors and extend their life. However, many patients do not see this benefit and some patients develop serious side effects. For most cancer patients, there is no way to predict if they will benefit from or be hurt by ICB. A test that could give doctors and patients a better understanding of the risks and benefits for ICB treatment for each individual is urgently needed. Examining the blood of patients, we discovered certain immune cells in patients who are less likely to benefit from ICB. We have found this is true for both melanoma and bladder cancer patients. We plan to examine whether these cells also matter for patients with other cancers and if there are differences in these immune cells depending upon a patient’s race. We also would like to better understand this special population of immune cells and how they may be linked to immune cells in the tumor. We hope that this will lead to the development of a safe and easy test that will provide patients better information about how ICB treatment will work for them. With this information, we hope to allow patients to feel and function better and live longer by finding a therapy that will be more likely to help and less likely to hurt them. 

Adrian Krainer, PhD

Funded by the Dick Vitale Pediatric Cancer Research Fund

We aim to develop a novel and effective therapy for a lethal pediatric brain cancer (diffuse midline glioma, DMG). No effective treatment for DMG currently exists. This cancer arises when a mutation appears in a gene called H3F3A, causing it to produce a toxic protein. The mutant protein makes cells grow unchecked, forming a tumor in an inaccessible brain region and eventually killing the patient. Each of our genes makes RNA—so-called messenger RNA (mRNA)—and the mRNA is then read in another part of the cell to make the protein encoded by that gene. The technology we use, called “antisense”, allows us to target the mRNA made from a gene, and either destroy it or change it. Either way, the toxic protein is no longer made, and because the tumor cells require it for growth, they stop growing and die or change into normal cells. Once our antisense drug is developed, it will be injected into the fluid surrounding the spinal cord, allowing it to reach the brain tumor. Another gene, called H3F3B, encodes the same protein as H3F3A, so our method will get rid of the defective protein but not the normal protein. Therefore, the drug should not harm normal tissues outside the tumor. We will design, test, and perfect our antisense approach using cells derived from DMG tumors, and mouse models of this brain cancer. If this project is successful, the resulting antisense drug will undergo further safety tests, in preparation for clinical trials involving DMG patients.     

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