Dendritic cells are a type of immune cell that patrols tissues to find signs of disease. When they find a tumor, they can pick up pieces of multiple different cell types including normal cells, bacteria, and pieces of the tumor called antigens. Their main job is to carry these tumor antigens to special T cells that can kill tumors. They show the antigens to the T cells to let them know there is cancer in the body and guide the T cells to attack the tumor. In places like the skin, dendritic cells can pick up both harmless skin antigens and dangerous melanoma tumor antigens at the same time. This is tricky because dendritic cells need to show the harmful melanoma antigens to T cells to fight the cancer, but they also have to hide the harmless skin antigens from T cells so they don’t mistakenly attack healthy tissue. Our research shows that when dendritic cells take in many different types of antigens at once, it’s harder for them to tell the T cells about the tumor. This can weaken the immune system’s response to cancer. We are studying how dendritic cells can better separate these antigens to improve how they activate T cells against melanoma. Our goal is to use this knowledge to create better treatments that boost the immune system’s ability to fight cancer. This could lead to more effective therapies that protect normal tissues and strengthen the immune response against tumors.
Funded by the Stuart Scott Memorial Cancer Research Fund
Acute myeloid leukemia (AML) is the deadliest blood cancer. People with AML are treated with chemotherapy, a treatment intended to kill cancer cells. However, some AML cells have qualities that prevent them from being killed with chemotherapy. These cells remain in the body even after treatment. Unfortunately, these “chemotherapy-resistant” AML cells can cause relapse. People with AML achieve remission when doctors can no longer detect AML after treatment. Relapse occurs when the previously undetectable AML returns after remission. Relapse is the primary cause of death for AML patients. Unfortunately, ~30% of all AML patients will relapse within three years of their diagnosis. Our research goal is to understand why some AML cells survive chemotherapy and others do not. We aim to identify new treatments that target chemotherapy-resistant AML cells.
Certain proteins produced by many cells in the body have sugars attached to them. In AML cells, we found that the kind of sugar attached to these proteins determines growth rates and response to chemotherapy. In this proposal, we will test how specific categories of sugars control AML cell growth, chemotherapy resistance, and relapse. We will use mouse models of AML to test how drugs that change the sugars available to AML cells could be used to treat AML. We expect the proposed studies will pave the way for identifying new medicines that can be used to stop AML cells from resisting chemotherapy, prevent relapse, and support AML patient survival.
Funded by the Stuart Scott Memorial Cancer Research Fund
The nucleus is the largest structure in the cell, and among other functions it protects our DNA, which makes life as we know it possible. Cells constantly experience mechanical/physical stress while growing or moving within the tissues of our body. Importantly, the nucleus constantly senses the mechanical stress that cells experience in our body. In doing so, the nucleus constitutes an important structure controlling cell function in both health and disease, such as cancer. The tumor is composed of many cell types (including cells of our immune system) and often imposes to cells and their nuclei physical stress. Such physical stress might lead to nuclear deformations, with important consequences to cancer progression. We will investigate how nuclear deformations (often observed in breast cancer) regulate the function of the cells in our immune system and their activity against cancer cells. This will contribute to understanding the biology of cancer progression and how the cells of our immune system fight cancer cells. Additionally, determining how mechanical stress regulates communication between different cell types is critical for understanding how diseases initiate and progress. Toward this end we will perform laboratory experiments with mouse and study patient cancer samples. Our project will provide a connection between the mechanical stress experienced by the nucleus (both in cancer cells and in cells of our immune system) and patient clinical data, opening new options for the treatment of cancer.
Funded by the Dick Vitale Pediatric Cancer Research Fund
Diffuse midline glioma (DMG) is a very aggressive brain tumor that occurs mostly in children. DMG treatment involves surgery, radiation, and chemotherapy, but most people with DMG don’t live longer than a year despite these treatments. We desperately need better therapies for this disease. Treating DMG is difficult because tumors aren’t the same in every person, so a drug that works for one person might not work for another. Therefore, we need treatments that are personalized for each patient. In addition, different parts of the tumor may not all respond to the same drugs, and we might need to use a mixture of drugs to eliminate the whole tumor. And even if we find drugs that do this in the lab, getting them into the tumor is tricky because of the “blood-brain barrier”, which prevents many drugs from getting from the bloodstream into the brain. We are proposing a new approach to DMG treatment that overcomes these challenges. To find individualized treatments, we will test many different drugs on tissue from surgery or biopsy to see which ones work best for each patient. We’ll also look at the effects of drugs on individual cells in the tumor and find the combinations of drugs that kill the most tumor cells. Finally, we’ll use a method called convection enhanced delivery (CED) to pump drugs directly into the tumor, bypassing the blood-brain barrier. By using these approaches, we will find better treatments for DMG and other brain tumors in kids.
Funded by the Dick Vitale Pediatric Cancer Research Fund
Our research focuses on a type of leukemia called B-cell acute lymphoblastic leukemia (B-ALL), which is most commonly found in children and adolescents. Despite advancements in treatment, a significant number of young patients do not respond well to existing therapies and face high risks of relapse. Our project specifically addresses those cases caused by changes in a gene called CRLF2, which are associated with poor outcomes. To understand and combat this challenging disease, we are using a cutting-edge technique called CRISPR/Cas9 to create detailed models of human blood cells that carry the same genetic changes seen in patients with CRLF2-related leukemia. These models allow us to study the disease in a controlled environment and understand the step-by-step development from the initial genetic changes in a human blood cell to full-blown leukemia. By examining these models at a microscopic level, using technologies that analyze individual cells, we aim to uncover new details about how these leukemias develop and find weak points where new drugs could intervene. Our goal is to identify new treatments that could target these leukemias more precisely and to explore ways to detect and perhaps prevent the disease before it fully develops. This research could lead to better survival rates and less suffering for children affected by this aggressive type of leukemia, providing hope for families facing this diagnosis. The knowledge gained could also help in understanding other similar types of childhood leukemias, broadening the impact of our work beyond B-ALL.
Funded by the Dick Vitale Pediatric Cancer Research Fund
Pediatric Glioblastoma Multiforme (GBM) is a very tough brain tumor that affects kids. The chance of surviving for 5 years or more with this type of tumor is less than 15%. GBM causes many deaths each year in the U.S., and there isn’t a good treatment available right now. Surgery is the main way to treat GBM, but it’s really hard to get rid of all the tumor cells because they spread into nearby healthy brain tissue. This often causes the tumor to come back after surgery. The fact that GBM comes back is the main reason why survival rates are so low. In our previous study, we came up with a new way to stop GBM from coming back after surgery. We created a special immune cell called CAR-Macrophage that targets and kills any remaining GBM cells after surgery. Our early tests in mice with GBM showed very good results in keeping the tumor from returning. In this proposal, we want to make this method even better. Our new approach includes three main improvements: (1) nanoparticles that help deliver cell engineering tools to modify immune cells; (2) a gel that can fill the space left by the tumor after surgery; and (3) a better way to make the modified immune cells work more effectively and last longer. If this works, it could greatly improve treatment and survival rates for kids with GBM.
Funded by the Dick Vitale Pediatric Cancer Research Fund
Our goal is to find better ways to treat children diagnosed with a blood cancer called acute myeloid leukemia (AML). AML is a devastating illness that affects around 500 kids in the United States every year. While many children respond well to current treatments, some don’t, and their cancer comes back, which can be very hard to treat. Our work focusses on a specific group of cells within the blood cancers called leukemia stem cells (LSCs). These cells can survive through treatment and cause the cancer to come back. So, we need new treatments that can specifically kill these LSCs. We’ve discovered that these LSCs rely on molecules called polyamines to survive. By decreasing the levels of polyamines using drugs, we can stop the LSCs from making proteins they need to stay alive. Our research suggests that a protein called eIF5A plays a big role in this process. Now, we want to test if drugs that block polyamine metabolism can stop AML from growing in models that mimic what happens in patients. We also want to understand exactly how eIF5A helps the cancer cells survive. If our experiments are successful, it could lead to new treatments for children with AML that have the potential to improve the outcomes for these children.
Funded by the Dick Vitale Pediatric Cancer Research Fund
Despite significant advances in the treatment of pediatric cancer, leukemia remains the second leading cause of cancer related death in children. T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive cancer that affects both children and adults. When T-ALL does not respond to chemotherapy or returns after initial treatment (relapses), there are few treatment options. New treatments are needed for T-ALL. The way cancer cells use energy or develop building blocks for growth is different from normal cells. We are working to understand how these energy and building processes within T-ALL cells are altered, with the hope that we can use this as a vulnerability for developing new therapies. We are particularly interested in drugs that alter how the cells produce a building block called methionine, and we are testing how these drugs work in T-ALL. Our ultimate goal is to find effective and non-toxic treatments for T-ALL.
Funded by the Dick Vitale Pediatric Cancer Research Fund
Childhood brain tumors are a major cause of death for children. Medulloblastoma is one of the most common brain cancers in children and also one of the most difficult to treat. These children typically need extensive surgery, chemotherapy, and other treatments. Unfortunately, even with these treatments, many children with this cancer die from their disease. I am a pediatric neuro-oncologist, and it is my career hope to bring new therapies for medulloblastoma from the lab into the clinic.
My research studies why some children with medulloblastoma do not respond to treatment. I have made several discoveries that point toward new biology within the cancer cells that promote its growth. I have particularly focused on a new category of genes that we have recently described, called microproteins. These are small proteins that were missed in prior research on this cancer, and we have found that they are important for the ability for cancer cells to survive. I am optimistic that these discoveries are pointing towards new treatment options. To grow this vision, this V Foundation award will allow me to focus on studying certain new genes that we hope will lead to new treatments. Through this work, I hope to make new discoveries in medulloblastoma that are important for patients.
We are trying to find out why some ovarian cancer patients don’t respond to chemotherapy. Even though many patients start off well with the treatment, most eventually become resistant to it. When that happens, the only option left is to focus on making the patient comfortable, not curing the cancer.
To solve this problem, we need to understand what causes this resistance so we can develop new treatments. In our study, we found an important factor linked to this resistance by looking at patient data. Early tests suggest this factor might affect immune cells and cause resistance. We will investigate how this factor works and test new ideas using animals, patient samples, and state-of-the-art technologies.
