Funded by Trea and Kristen Turner
Medulloblastoma (MB) is a common form of brain cancer and the leading cause of cancer-related death and injury in children. One subtype of MB (MYC-amplified MB) occurs in the cerebellum, the part of the brain that controls movement. However, MB often spreads to other parts of the brain and spinal cord. In roughly one-third of patients, MB has already spread when they are diagnosed. In patients that develop MB more than once, most of them have tumors beyond the brain. The current treatment is radiation of the entire brain and spinal cord, followed by high-dose chemotherapy. This is very harmful to a child’s developing brain and not effective for the spread tumors. New and improved therapies are greatly needed.
Understanding how MB spreads will help researchers develop new treatments and prevention plans. LDHA is an enzyme that plays an important role in tumor development and spread. In healthy tissue, LDHA levels are low. In tumor samples, LDHA levels are extremely high. Blocking LDHA may slow cancer without damaging healthy tissue. Our goal is to discover in the laboratory if targeting LDHA can prevent and treat MB that has spread. Then we will develop clinical trials so that children suffering from this horrible disease can have better results.
Funded by Hooters of America, LLC
Cancer treatments have improved over the past 30 years, but many patients still die from the disease. A new type of drug has been found that causes the patient’s body to attack the cancer. This new drug, called “immunotherapy”, works very well for some people but not for many others. Our studies try to find ways to make this treatment work for more patients. We are especially interested in how radiation can be used to improve immunotherapy and have found a new way that these two treatments work together. Our current work is focused on finding other ways that these treatments work together. We are especially interested in learning how we might improve how patients feel during and after treatment by reducing the side-effects of therapy. Overall, the major goal of our work is to increase the success of cancer treatment for all patients and to improve their overall quality of life.
Funded by the Dick Vitale Pediatric Cancer Research Fund
There is a unique group of cancers that progress quickly during childhood due to faults in the mechanisms which repair damaged DNA. As a result, these childhood cancers have the highest number of DNA mutations (hypermutant) of all human cancers. Immunotherapy has demonstrated hopeful results in these patients. Yet, 50% of these cancers will progress after initial response to immunotherapy. This poses a significant problem. Adoptive cell therapy takes advantage of using immune cells to kill cancer cells. Cell therapy has shown promising responses in many adult cancers. This effect is greater when cell therapy is used in combination with prior immunotherapy treatment. Our research team has developed new mouse models that successfully mimic these childhood brain cancers. One of the aims of our research project is to use these mouse models to study the role of cell therapy. We will determine overall survival and response to therapy. We aim to prove the feasibility of expanding childhood immune cells as a proof of concept through the use of our International Consortium. We will use complex computer software and genomic tools. These methods will provide a thorough review of immune cells. We will be able to predict which patients would benefit from cell therapy. This project will increase knowledge in this research area. In addition, it will answer important questions which will lead to improved patient outcomes and treatment options. Most importantly, this project will lead to the first-ever childhood cell therapy clinical trial.
Funded by the Dick Vitale Gala in memory of Chad Carr
Cancer is the leading cause of disease-related death of children past infancy in North America. All cancers contain mutations in their DNA, but the causes of these mutations are usually not known. This gap in our knowledge negatively impacts patient care: It is difficult to predict how a tumor will change – how it will respond and whether it will come back – if one does not understand why or how it developed in the first place. Recently, our lab and others have shown that some childhood cancers contain a fingerprint which can be used to pinpoint what caused its mutations and when they developed. The identification of these fingerprints, or mutational signatures, is a rapidly evolving area of research that has benefited from new technologies, such as whole genome sequencing. This project will identify mutational signatures in aggressive childhood cancers. We will seek to understand whether cancer- causing mutations have common fingerprints, and if these can be used to select patients that would benefit from ongoing clinical trials.
Many cancers are treated with radiation therapy. Some cancers types are especially hard to treat. One type of cancer that affects the lungs and throat is only cured in about half of cases. Even when drug treatments are added to the radiation therapy, cure rates are not much improved. Also, adding drugs to radiation therapy can make the treatment hard for patients to tolerate. New treatment approaches are needed for these patients.
One new approach that is showing promising results is to give refined treatments that are more precisely targeted to each patient’s cancer. This approach is called Precision Medicine. Precision Medicine has not been used much for the cancer type that affects the lungs and throat. Also, Precision Medicine has not yet been used for radiation therapy. Instead, the standard treatment for these patients continues to be a one-size-fits-all approach.
We expect that the standard one-size-fits-all treatment approach could be replaced by Precision Medicine. The objective of our research is to develop new Precision Medicine approaches for the cancer type that affects the lungs and throat for use with radiation therapy. These new treatments could someday lead to higher cure rates and tolerability of treatment. If successful, our research will lead to new clinical trials that will test these new treatment approaches in cancer patients.
V Scholar Plus Award – extended funding for exceptional V Scholars
Neuroblastoma, an embryonal tumor that arises in the peripheral sympathetic nervous system (PSNS), accounts for ~12% of cancer-related deaths in childhood. About half of all patients, especially those over 18 months of age with amplified copies of the MYCN oncogene, present with evidence of widespread metastasis at diagnosis and have a very high risk of treatment failure and death despite receiving greatly intensified chemotherapy. Attempts to improve the treatment of metastatic neuroblastoma have been slowed by the lack of a full understanding of the multistep cellular and molecular pathogenesis of this complex tumor. Recently, we developed a novel zebrafish model of neuroblastoma metastasis by overexpressing human MYCN oncogene, which is amplified in 20% of neuroblastoma cases, and knocking out gas7 gene, which is deleted in a subset of high-risk neuroblastoma patients. This zebrafish model affords unique opportunities to study the molecular basis of neuroblastoma metastasis in vivo and to identify novel genes and pathways that cooperate with MYCN overexpression or GAS7 loss to promote this fatal stage of disease development. This research approach is expected to reveal novel molecular targets that can be exploited therapeutically. To achieve this goal, we propose to establish reliable in vivo zebrafish models of the aberrant genes and pathways that contribute to neuroblastoma metastasis. In the near future, these models will be used to screen for effective small molecule inhibitors that block specific steps in metastasis with only minimal toxicity to normal tissues, and thus would be assigned high priority as candidate therapeutic agents.
Funded in partnership with WWE in honor of Connor’s Cure
Medulloblastoma is the most common malignant brain tumor in children. Medulloblastoma is really made up of four diseases, of which two types: Group 3 and Group 4 account for the majority of cases. The main tumor ‘lump’ in the brain is called the ‘primary tumor’. The primary tumor can spread (metastasize) to cover other regions of the surface of the brain and spinal cord. Most children who die from medulloblastoma die because the tumor has spread (metastasized) and not due to the primary tumor. The most damaging therapies (radiation) for children with Group 3 and Group 4 medulloblastoma are necessary to treat the metastases.
For the most part, medulloblastoma only spreads to the surface of the brain and spinal cord, and not to other organs. According to the textbooks this occurs when cells drop off the primary tumor, float around in the spinal fluid, and then reattach to the brain or spinal cord and start growing again. There really is no evidence or experiments to support this mechanism, just historical speculation. We have now shown that in fact, medulloblastoma spreads through the blood stream—the cells enter the blood stream, and then home back to the brain and spinal cord where they grow and kill the child.
This new understanding of the metastatic process for medulloblastoma offers fresh opportunities to non-invasively diagnose medulloblastoma in the blood, to prevent the metastatic cascade, prevent the progression of metastases, and decrease the toxicity of therapy for children with medulloblastoma.
Funded by LG Electronics Home Court Advantage
Funded by Papa John’s International
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