Myelodysplastic syndrome (MDS) is a blood cancer in which the bone marrow is unable to make enough healthy blood cells, and patients are at risk of developing a more aggressive leukemia. Besides stem cell transplantation, there is only one treatment option that has been proven to be effective at extending life for patients with MDS. Unfortunately, this drug still often fails, leaving patients with no other options. Recently, a new idea to enhance the immune system’s ability to fight cancer has been developed and successfully applied to other types of cancer. These new treatments (called immune checkpoint inhibitors) help the immune system better recognize and attack cancer cells. However, these treatments do not work in MDS. Here we propose a new immune checkpoint protein, which is found at high levels in the bone marrow MDS patients. Using mice transplanted with human MDS cells, we will study whether this protein hinders the ability for the immune system to fight MDS and whether we can block this protein to treat MDS. This study will let us understand how MDS avoids the immune system and help us find new treatments to enhance the immune system, leading to better outcomes for patients with MDS.
Funded by the Dick Vitale Pediatric Cancer Research Fund
Brain tumors are the leading cause of cancer-related death in children. While recent advances in neuro-oncology have helped us understand the biology of what is causing brain tumors to develop and grow, many children with brain tumors will still have a dismal prognosis. These tumors can be refractory to upfront treatment, such as radiation or chemotherapy, and there is need for better options. CAR T-cell therapy is a new type of treatment that uses the patient’s own immune cells and modifies them in the lab to recognize and kill cancer cells. CAR T-cell therapies are highly specific to the cancer cells. In our clinical study, we are evaluating the safety and anti-cancer activity of CAR T cells for pediatric patients with brain tumors.
Funded by the Dick Vitale Pediatric Cancer Research Fund with support from the Glover and Frazier families
T-cell acute lymphoblastic leukemia and lymphoblastic lymphoma (T-ALL/LBL) are types of blood cancer that are very hard to treat. Patients with these leukemias need to get strong chemotherapy that can have bad side effects. Because of this, we need to find new treatments that are less toxic. CAR T-cell therapy is a new type of treatment that uses the patient’s own white blood cells and allows them to detect and kill cancer cells. These therapies can focus on only killing the cancer cells and not normal tissues and have few side effects. We have invented a way to treat this type of leukemias and have shown that it works well in models in the laboratory. We want to find out if our CAR T-cells are safe and effective in patients with childhood T-ALL/LBL. To help us reach our goal, we have formed a group of experts, including a) Lab experts – who design CAR T-cells, b) Clinical experts -who know how to treat leukemias c) Immunology experts – who can tell us how the CAR T-cells work and d) Pathology experts – who can study how the leukemias respond to the treatment. Our hospital has what is needed to start the clinical trial that we are planning. We want to find a cure for T-ALL/LBL that has few side effects and help save the lives of children with this type of leukemia.
Colorectal cancer is the second most deadly cancer worldwide. Both bacteria in our gut and the activity of our own cells in the intestines can contribute to the risk of colorectal cancer. However, we don’t know how these two factors work together to cause cancer. Some “bad” bacteria use toxins to cause colorectal cancer. But cancer takes over 1,000 times longer than bacteria’s lifespan to develop. So why do bacteria purposefully cause cancer? We think that “bad” bacteria remodel intestinal cell activity to produce nutrients that the bacteria can use as “food.” The rewired intestinal cell metabolism helps cancer cells grow faster. In other words, cancer development is a side effect of the “bad” bacteria trying to get food. If we can better understand this process, we can develop treatments that stop the growth of the “bad” bacteria and the tumors they cause. Using experiments in mice, we will first test whether the “food” produced by the cells in our gut helps the “bad” bacteria grow better. We will then try to block this process to reduce the growth of both the “bad” bacteria and the tumors. Lastly, we will test whether what we find in animals holds true in humans. This proposal is innovative because it uses what “bad” bacteria “eat” to help us understand how they cause cancer. We hope to use what we learn to develop better, more effective treatments for patients suffering from colorectal cancer caused by “bad” bacteria.
Funded by the Dick Vitale Pediatric Cancer Research Fund
Neuroblastoma is a common and deadly childhood tumor. Even with our best treatments, the disease may return. If this happens, our best treatments are not always effective and most patients will pass away. This motivated us to study how neuroblastoma becomes resistant to treatment. Neuroblastoma tumors are made up of different kinds of cancer cells, some of which are sensitive to chemotherapy, and some of which are resistant. Importantly, these different populations can switch between each other, causing sensitive cells to become resistant. How cells do this is not well understood, but may be related to proteins called “transcription factors.” Understanding how resistance occurs may allow us to create new treatments. These treatments could change resistant cells into sensitive cells or stop sensitive cells from becoming resistant. In this proposal, we will use new tools to understand how neuroblastoma cells switch between sensitivity and resistance. We will also use these tools to identify the controllers of these switches. We hope these studies will lead to new ways to treat children with neuroblastoma by targeting resistant cells. We believe this will create new ways to stop this terrible childhood cancer.
Funded by the Dick Vitale Pediatric Cancer Research Fund
The Schwartz Lab studies two genes, SAMD9 and SAMD9L that are known to cause a bone marrow failure syndrome in children called myelodysplastic syndrome (MDS). There are no reliable pediatric MDS model systems, thus we have created one from a special type of stem cell that contains mutated SAMD9 or SAMD9L. It is important to have these new cell lines, because cells that we can obtain from patients do not grow well or for a long time making studying them very hard. We will perform several tests in our new model system to determine why mutations in SAMD9 and SAMD9L cause blood stem cells to die. Together with our cell lines we have also developed a second set of tools that will allow us to turn on or to turn off SAMD9 or SAMD9L without using interferon—an inflammatory substance in the cell that turns on many other cell processes including SAMD9 and SAMD9L. We have completed initial experiments that suggest that SAMD9 and SAMD9L are important in how cells communicate during inflammation and other immune responses. Our proposed experiments will further determine how disease-causing mutations in SAMD9 and SAMD9L disrupt communication in these important cellular pathways. Understanding how SAMD9/9L mutations effect the blood stem cells will help us determine the right treatment approach for patients with pediatric MDS, because some patients with SAMD9 or SAMD9L mutations may not need treatment at all.
Funded by the Dick Vitale Pediatric Cancer Research Fund in memory of Austin Schroeder
Over the past decades, the cure rate of pediatric leukemiahas significantly increased because ofimproved understanding of diagnosis, chemotherapy combinations, and supportive patient care. However, patients with MLL-rearranged subtype leukemia still face an unfavorable outcome and few therapeutic options. To date, the five-year survival of patients in this subtype is less than 70%, much lower than most other patients. To better improve the treatment outcome and increase the survival, many novel therapeutic drugs have been identified. Among these drugs,the inhibitors against BET proteins hold a great promise. So far, the mechanisms controlling drug response and resistance are not well understood.To our knowledge, our proposed research fits the goal of the V-foundation. We have conducted a successful genome-wide screen. We are going to study thefunction of novel candidate genes in drug resistance models in vitro and in vivo, as well as the working mechanism.Completing our proposed work is expected to significantly prevent and treat drug resistance and relapse, saving more patients with this deadly disease.
Funded by Matthew Ishbia and the Dick Vitale Pediatric Cancer Research Fund
Childhood cancers of developing muscle are some of the most difficult to treat childhood cancers. Therapy has not significantly changed in the past 20 years and there isn’t even a meaningful new treatment being considered. Currently, even after the most intensive therapy possible, a third of these tumors will return and take the life of a child or young adult. We have taken a new approach using state-of-the-art methods to identify what we hope will be more targeted and less toxic treatments that yield better outcomes. We have already identified three new therapeutic avenues that we will test. The first is to ask if the abnormal gene that drives this disease, called PAX3-FOXO1, is a good drug target. We engineered the gene to be sensitive to a derivative of a known drug. While we can’t do this in kids, it allows us to ask what would happen if we had a drug? Second, we found that PAX3-FOXO1 turns on a small number of other genes, and we already have drugs that can target some of these. Third, we identified other possible drug targets that PAX3-FOXO1 recruits. We will test if these are key to causing cancer and if they would be good drug targets. We believe that our comprehensive approach gives us the best chance in the past 30 years to change the lives of these children with cancer, and to identify drugs or drug combinations that will be less toxic and yield better outcomes for these patients.
Funded by Mark and Cindy Pentecost in memory of Chika Jeune
Pediatric brain tumors are the most common cause of cancer related death in children. Diffuse midline glioma (DMG), a type of childhood brain tumor, is universally fatal. Our lab has demonstrated in mouse models that DMG is responsive to two classes of treatments known as epigenetic and metabolic therapies. A major challenge in patients, however, is that single drugs are unlikely to be effective against this highly aggressive malignancy. Our grant proposal seeks to test the efficacy and biology of a combinatorial treatment of three drugs against DMG in an effort to generate pre-clinical data which could be potentially advanced to clinical trials in patients. In addition, our grant seeks to understand how these therapies influences the population of cells within a given tumor that may confer therapeutic resistance. We envision that these therapeutic and molecular insights will advance our understanding of DMG and lead to novel treatment paradigms.
Supported by Bristol-Myers Squibb through the Robin Roberts Cancer Thrivership Fund
Survivors of childhood cancer are at high risk of late health problems related to cancer treatment. Our early work suggested that health problems differ among survivors based on social-economic status like level of education, household/personal income, and the neighborhood in which they live. In the proposed research, we will describe and measure differences in health problems among childhood cancer survivors based on the social-economic status. We will focus on common health problems including obesity, high blood fat levels (triglycerides or cholesterol), abnormal blood sugar control, high blood pressure, heart muscle weakness, and heart attack. We will use stored blood samples and data already available from the St. Jude Lifetime Cohort Study to study biologic changes that may predict a survivor’s risk of health problems and links to social-economic factors. We hope that the results of this work will help identify survivors at higher risk for health problems and guide new research aiming to reduce, reverse, or prevent the harmful effects of social-economic factors on health problems after treatment for childhood cancer.
