Funded by the Dick Vitale Pediatric Cancer Research Fund
When the body is unable to fix damaged DNA, it can cause some childhood cancers to grow very quickly. These cancers have many DNA changes (called “mutations”) so we call them “hypermutant”. Some children are born with a syndrome, called CMMRD, which makes them develop a lot of these hypermutant cancers at a young age. A treatment called immunotherapy has shown positive results in these patients. However, it doesn’t work for everybody and when a cancer is found late, about 40% of children will get worse, even after treatment. Immunotherapy can also cause side effects, some of which are serious. Recently, we discovered that mRNA-LNP vaccines (similar to those used for COVID-19) may actually be able to prevent cancers in children with CMMRD. These vaccines have very few side effects and might help many patients. However, we still need to learn more about what components make an effective vaccine and then test it in human and animal models. In this project, we will do three things. We will first determine what should be included in a vaccine to make it work well. We will then test the vaccine in mice to see if it can prevent cancer. Finally, we will see how well the vaccine works and how safe it is for humans. To do this, we will work with international collaborators who have experience making vaccines. This work has the potential to help children with many other cancer-causing syndromes, as well as common adult cancers.
Funded by the Dick Vitale Pediatric Cancer Research Fund
Glioblastoma is a cancerous brain tumor and the major cause of cancer-related death in children, teens, and young adults. Standard treatments like surgery, chemotherapy, and radiation don’t work here. Our international consortium found a group of glioblastomas caused by problems with how DNA is copied. These are called replication repair deficient (RRD)-gliomas. We showed that they have many mutations and can respond after stimulating the body’s immune defenses using immunotherapy.We recently discovered three types of RRD-gliomas (RRD1-3). Each type acts differently and responds to treatment in its own way. We believe using specific treatments for each group will help patients live longer with fewer side effects. Our plans are:RRD1: These tumors have many immune cells. We will reduce use of harmful treatments like radiation.RRD2: These tumors have fewer immune cells. We will use two kinds of immunotherapy together to help the body fight the cancer.RRD3: These tumors have little immune activity. We will use immunotherapy with drugs that target special features of the tumor. These ideas are based on strong lab studies, tests in animals, and early results in patients. Now we will study how each tumor type responds differently to more precise treatments. We will track and adjust this in real time by testing tumor DNA in the fluid around the brain and spine. This project will advance research and improve care for young people with these deadly brain tumors. In the future, it will be expanded to help treat other types of deadly cancers.
Funded by Hockey Fights Cancer™ Powered by the V Foundation
Meningiomas are the most common intracranial tumor in adults. While most meningiomas can be successfully treated with surgery, there are a significant proportion of cases that require the addition of radiation therapy to delay tumor recurrence. However, our current methods of selecting which patients should be escalated for radiation after surgery remain relatively imprecise, especially for intermediate-grade meningiomas that can behave in a highly variable manner. Molecular profiling, specifically DNA methylation of meningiomas has proven to be an effective and efficient method of providing additional information on these tumors that can be used to better predict whether they will or will not recur after surgery. However, whether a similar set of molecular signatures exist to predict whether a meningioma of any given patient will respond to radiotherapy after surgery remain to be determined. This V Foundation grant will enable us to 1) develop a clinically important predictor using specific molecular signatures of any given patient’s meningioma to tell us whether their tumor will respond to radiation, 2) test this predictor through a novel, real-time, molecular-pathology informed clinical trial, and 3) determine if the same signatures that can prediction response to radiotherapy in the tumor tissue can be used to non-invasively provide the same information through a simple blood test. Results from this study have the potential to dramatically improve the way we treat patients with meningiomas and will represent a significant shift forward in the field of neuro-oncology.
Funded by the Dick Vitale Pediatric Cancer Research Fund with support from Hockey Fights Cancer in honor of Ben Stelter
Neuroblastoma (NB) is a type of childhood cancer that is difficult to treat after it has spread throughout the body. Using animals that develop aggressive NB, we found different types of tumor cells that may lead to cancer spread. We are proposing to look very closely at these different tumor cells and determine how they may lead to NB spread and drug resistance in patients. We will also test new targeted drugs for their effects on NB spread and through our studies, new ways to treat aggressive childhood cancer may be found.
Vintner Grant funded by the V Foundation Wine Celebration in honor of Leslie Rudd and Family
Cancer is one of the leading causes of death across the globe. Early cancer detection can facilitate effective treatment and fewer side effects to improve patient survival and quality of life. Therefore, there is tremendous interest in using recent technological advances in DNA sequencing, medical imaging, and machine learning methods to enable early detection efforts in cancer. Early detection efforts are likely most effective among individuals genetically predisposed to cancer. Moreover, DNA mutations during the aging process can also increase the risk of developing cancer. Therefore, we aim to use population-level sequencing data to build computational methods to assess individualized risk for developing cancer. We envision that the proposed approach will provide novel insights into the role of inherited and acquired DNA mutations toward tumor growth in high-risk individuals. These insights can be employed to facilitate early detection efforts in cancer.
Immunotherapy is a type of cancer treatment that uses the body’s own immune system to fight and destroy cancer cells. Despite its success in treating a number ofcancers, immunotherapy has had a limited impact on the treatment of blood cancers, known as leukemia. While there are many reasons for this, a primary reason is the current lack of understanding of how the cells of the immune system interact with leukemia cells. Present knowledge of the types ofimmune cells that live in the bonemarrow and their behavior at various stages of leukemia are almost entirely lacking. To address this, wewill perform awidespread analysis of immune cell composition and function during leukemia disease progression. We will use cutting-edge technologyto understand thebiological mechanisms that become altered during leukemia, which may cause immune cellsto promotethe cancer’sinitiation and relapse. These studies would enable the identification of “immune signatures” associated with different stages of cancer development. The findings will lay the groundwork for our understanding of the bone marrow immune landscape in the context of the human disease. We envision that these studies will fundamentally lead to new treatment strategies for this devastating cancer and thereby improve patient outcomes.
In the last three decades, no new drugs that can effectively treat pancreatic cancer have been found. One of the major problems in pancreatic cancer is that most research is performed on patients where the cancer has not spread to the rest of the body. This is because these patients are eligible for surgery and researchers have access to the tissue for experiments. However, most patients with pancreatic cancer are diagnosed when the disease has already spread. Patients where the disease has spread do very poorly compared to patients where the disease has not spread. We believe that there are changes in the cancer’s DNA that cause the disease to spread.
To investigate this, our laboratory compared the DNA from patients where the disease had or had not spread, and found that a gene that can potentially promote the spread of this cancer. This gene, named KRAS, multiplies inpatients where the cancer has spread. Patients where this gene has multiplied are very resistant drugs used to treat this cancer. The goal of our project is to understand how the multiplication of this gene is related to therapy resistance. Using specialized techniques in our laboratory, we will grow tumor cells from patients with and without multiple copies of KRAS to figure out changes in the cell that are related to this specific genetic change. We intend to use this information to find new drugs to treat patients where the cancer has already spread.
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.
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