Funded by the Dick Vitale Pediatric Cancer Research Fund with support from Hockey Fights Cancer and Jeffrey Vinik
The most common cancer in children, including teenagers, is a blood cancer named leukemia. Chemotherapy is the main treatment for pediatric leukemias. Although most patients respond well, some do not, leading to poor outcomes. Chemotherapy can also have negative side effects both during treatment and for the rest of their lives.
Patients who don’t get better with chemotherapy are those that have one of most common genetic changes, the rearrangement of a gene called KMT2A (KMT2A-r). In a study at The University of Texas MD Anderson Cancer Center, patients with KMT2A-r leukemia survived for 6 months after 2 chemotherapy treatments and only 2.4 months after 3 or more treatments. Scientists are looking at new ways to treat these patients and help them live longer.
Menin inhibitors could be a good option because they target KMT2A-r leukemia and have fewer side effects than chemotherapy. But some patients with KMT2A-r leukemia can also have mutations in other proteins that don’t let the menin inhibitors work as well by themselves.
With the help of the V Foundation, Drs. Andreeff, Carter and, Cuglievan, at MD Anderson Cancer Center plan to test different combination treatments that target menin and other proteins at the same time to get better results. This can potentially help children with KMT2A-r leukemia live longer and have better lives.
Funded by the Dick Vitale Pediatric Cancer Research Fund
Malignant rhabdoid tumors and epithelioid sarcomas are rare cancers that can develop throughout the body. Sadly, these tumors are often deadly for patients who can’t have surgery or whose tumors don’t respond to chemotherapy. Recently, a new drug called tazemetostat has been approved to treat these cancers, but only about 15% of patients get better with it. Our new research project explores DNA damage repair and targeting its mediators in tumors cells to offer new treatments to patients. Our past research shows that a protein called ATR is important for the growth of tumor cells. It is possible that other similar proteins are necessary for tumor growth and is therefore important that we study them to understand if ES and MRT patients may benefit from other drugs that interfere with these processes. For example, we found that combinations of drugs, chosen logically based on research evidence, is more effective in controlling tumor cell expansion, when compared to using drugs alone. We plan to find the best combination of novel drug inhibitors to stop these tumors from growing. We also want to understand how these drugs work in the body so we can predict which patients will benefit the most. This research should lead to a new, safe, and effective treatment for many patients with RT and ES who currently have no cure. The findings might also help treat other types of childhood and young adult cancers, creating a roadmap for difficult to treat tumors.
Funded by Constellation Brands Gold Network Distributors
Uterine serous carcinoma (USC) is a severe type of cancer that affects older women and is responsible for 40% of deaths from uterine cancer. Many women with USC have advanced cancer at diagnosis and must be treated with toxic chemotherapy and radiation. However, over half of women with this cancer initially only have a tumor in their uterus. Surgery can remove the tumor from the uterus. However, 1 in 4 women have their cancer return after surgery. Right now, doctors cannot identify which women will have their cancer return after surgery, and so usually all women receive toxic treatments after surgery to help prevent their cancer from coming back. If doctors could identify which women with this cancer will have their tumors come back after surgery, they could only give therapy to women who are likely to have their cancer return. At the same time, women who are not likely to have their cancer return could just be followed by their doctor and would not need toxic treatments. This would represent a major advancement. We have found a marker named GATA2 that can predict which women with this cancer will have their cancer return. Our proposal will figure out why this marker predicts cancer recurrence and support separate clinical trials to test whether we can spare many women with this cancer from chemotherapy. Our goal is to bring about the first real improvement in care for women with USC over the last 30 years.
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 Hooters in honor of 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 with support from Hockey Fights Cancer and Jeffrey Vinik
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.
