Funded by the Dick Vitale Pediatric Cancer Research Fund
Acute myeloid leukemia (AML) in children is difficult to treat, and thus it is important to identify new and less toxic therapies. We have identified a protein called CD97 that is present on AML cells and is required for their maintenance. Because CD97 is present in multiple forms, we will determine which are required in AML cells. We also will make and test the ability of antibodies we have made against CD97 to eliminate AML cells. We expect our studies willnot only reveal the role of CD97 in the development of childhood AML, butidentify a potential newdrug that may be used to treat kids with AML.
Lung cancer is a deadly disease. One common cancer treatment called immunotherapy boosts the body’s natural defenses to fight the tumor. However, while some lung cancer patients respond well to immunotherapy treatments, other patients do not respond to the therapy. This suggests that we need to find new ways to improve these treatments. Our research supported by the V Foundation aims to improve the body’s ability to fight lung cancer. We will study mechanisms to boost the effects of immunotherapy and we will test these new approaches using cancer models. This work has the potential to improve immunotherapy and expand the use of these treatments for larger numbers of lung cancer patients.
Funded by the Dick Vitale Pediatric Cancer Research Fund
Ewing sarcoma is the second most common bone tumor in children, adolescents, and young adults. Patients who are diagnosed with a tumor that has not spread are usually cured. Those who are diagnosed with metastases (the tumor has spread from its initial location) are rarely cured despite decades of clinical trials and intensifying treatment regimens aimed at improving their survival. In preliminary animal experiments, we found that a drug called DFMO, already approved by the FDA for the treatment of African Sleeping Sickness, can inhibit Ewing sarcoma metastasis. We will test the hypothesis that DFMO acts by interfering with critical metabolic pathways in tumor cells, that it is safe to combine DFMO with chemotherapy, and that the combination of DFMO and chemotherapy will work better than chemotherapy alone in prolonging the lives of mice with Ewing sarcoma. Assuming we can show that the combination of DFMO and chemotherapy is better than chemotherapy alone in our mouse model, this will provide the rationale for future clinical trials testing the effectiveness of adding DFMO to standard chemotherapy regimens for Ewing sarcoma patients.
Breast cancer is the most common type of cancer in women, causing many deaths each year. When the cancer has spread in the person’s body, the available treatments have many side effects and often cannot cure the disease. Research has shown promising results using immunotherapies, which make the patient’s own immune system attack the cancer. T cells are important cells of the immune system and can be very effective at attacking and killing cancer cells. Some breast cancers have a protein called HER2 that can be used as a target for T cells to attach. We plan to take the patient’s own T-cells and train them in the laboratory to attack breast cancer cells that have HER2. This treatment has proven safe in other cancer types and should have minimal side effects. However, breast cancer tumors are made up of different kinds of cells, not just cancer cells. Thus, we also plan to arm the T-cells with extra measures to get rid of the other bad cells in the tumor, making it easier for the T cells to eliminate all of the cancer. Based on previous research, we know that when successful, results using this kind of T cell-based therapy are long lasting for patients and can even cure their disease. With the recent FDA approval of T-cell therapies for several cancers, we are confident that the proposed project has the potential to improve the lives of patients with breast cancer.
Funded by the Dick Vitale Pediatric Cancer Research Fund
Outcomes for children with brain cancer are poor and current therapies are harmful to normal cells in thebody. New therapies that only target cancer cells are greatly needed to improve outcomes for this terribledisease. We tested the ability of a modified cold-sore virus to target and kill brain cancer while not injuringnormal cells in children. Results from the clinical trial were very exciting. We found that the virus directlykills cancer cells and also stimulates a child’s own immune system to attack the tumor. From the trial, welearned that in order to achieve even greater responses from the therapy, we need to continue theimmune system attack on the tumor. To achieve this goal, we will combine two therapies that work welltogether: the altered cold-sore virus with a unique cancer vaccine. When the cancer vaccine is givenbefore the virus, it prepares the immune system to fight the cancer and improves the virus’ ability to killthe cancer and stimulate the immune system attack on the cancer. We plan to create the ideal cancervaccine with the cold-sore virus in the lab and then conduct a clinical trial of the combination therapy tobenefit children in great need of more effective and less-toxic treatments. Weexpect these excitingtherapies will result in even better outcomes in children with brain cancer.Importantly, this combinationtherapy can be used to treat other pediatric cancers, increasing the overall potential to help children withcancer and their families.
Funded by the Constellation Gold Network Distributors
Although cancer immunotherapies are beneficial for many patients, about half of patients fail to respond to treatment or may only respond for a short time. Identifying which patients are benefitting from treatment is an important goal, as non-responders are subjected to needless treatment and deprived of potentially beneficial alternative therapies. To address this challenge, we have developed a new PET scan to identify which patients are experiencing a tumor remission rapidly after the start of treatment. We will first evaluate patients with non-Hodgkin’s lymphoma that are receiving CAR T cell therapy. If our imaging technology successfully identifies patients that are responding to treatment, we expect it could also help patients with other types of cancer that are receiving immunotherapies. Another long term goal will be to test if our imaging technology can help physicians understand if new immunotherapies in clinical trials can eliminate tumors.
Merkel cell carcinoma (MCCs) is a cancer that requires additional research. It is the most deadly skin cancer. Moreover, its incidence is rising, doubling from 2000 to 2013. Until recently, there have been no effective therapies for this disease. Immunotherapies have revolutionized the treatment of MCCs. Roughly 50% of patients respond to these treatments, called PD1 inhibitors. While this is an important advance, there are critical barriers to cure. There are no biomarkers to predict who will respond to treatment. Moreover, there are no treatments for patients who fail immunotherapy. To address this critical unmet need, we have assembled a large clinical cohort of patients with MCCs across multiple institutions. We will subject them to a number of assays designed to identify what immune cells are in each sample and what they are doing. Our goal is to identify patterns that predict who responds to therapy and why or why not. The biomarkers we discover can be immediately deployed to ensure that PD1 inhibitors are only given to patients likely to respond to them. For the rest, our studies will seek to identify novel immunotherapy drug targets. If successful, we can develop new drugs that can be used against these novel targets and test them in future clinical trials. This knowledge will be critical to improve patient care and a key advance to developing a cure for this deadly disease.
Funded by the Constellation Gold Network Distributors
Genetic information is carried in DNA, which is present in every cell of our bodies. Most cells have 46 chromosomes, which carry DNA within the cell. However, more than 90% of tumors have cells without the correct number of chromosomes. These cells are called “aneuploid”. Some whole chromosomes or large chromosome fragments may be duplicated or lost. Aneuploidy is a contributing factor in cancer formation. However, its exact role in this process is an unanswered question in cancer biology. The goal of this research is to understand the effects of different changes in chromosome number.
For our studies, we make use of a new technology that allows us to cut chromosomes at specific locations. With these experiments, we can study the effects of changes in large chromosome segments. Our current focus is a type of cancer called squamous cell carcinoma (SCC). In this cancer type, large pieces of chromosome 3 are affected. Here, we will uncover the interaction between chromosome 3 changes and DNA mutations. We will also create a human cell model of SCC. These studies address a gap in our understanding of aneuploidy in cancer by studying the effects of specific sets of chromosomal changes. With knowledge of how these chromosomal changes contribute to cancer formation, we will uncover new ways that cells can become cancerous. A better understanding of paths to disease formation will be crucial for designing new cancer treatments.
Harnessing the immune system to eliminate tumor cells has led to remarkable responses in several advanced cancer types. T cells are the key immune cell type which are engineered in the lab to seek out and destroy tumor cells, however in many cases tumor cells adapt to evade T cell killing, leading to disease relapses. Advances in cell engineering now permit T cells to be made in the lab from specialized stem cells. This technology promises to provide more cancer patients access to T cell therapies, but also presents the opportunity to make T cells more effective in prevent tumor escape. The goal of this research project is to study the ways in which tumor cells evade killing by lab-grown T cells, and how engineering specific molecules on lab-grown T cells may enable us to turn on tumor killing mechanisms to prevent tumor cell escape. Our overall goal is to further the development of this new kind of T cell therapy to be more effective across a wider range of cancer patients.
Funded by the Constellation Gold Network Distributors in honor of the Dick Vitale Pediatric Cancer Research Fund
Brain cancers have recently surpassed blood cancers as the most common cause of cancer-related death in children. The big question we ask here is how we can make cancers easy to destroy from the inside by the body’s own soldiers. Modern cancer-treating drugs utilize the body’s defense mechanism to destroy tumors and have shown promising results against several cancers. However, most of these drugs have been developed against adult tumors and do not always behave similarly against childhood cancers. Furthermore, a lack of suitable targets that can differentiate childhood brain cancers from normal cells prevents the safe treatment of childhood cancers. This is more so due to our lack of understanding by which cancer cells hide from the body’s soldiers, especially in brain cancer. While significant progress has been made in the care of children with medulloblastoma, some of those patients still suffer a lot. The cells create a signal on their surface which identifies healthy cells from diseased cells. It tells a particular type of cell called macrophages not to eat these cells. Macro meaning big and phages meaning eater mean Big Eater. The body uses some proteins to protect cells that should remain and help dispose of diseased cells. Cancers use this to create a force field to protect themselves. In this grant we will test how to reduce this force field on the surface so we can use the bodies soldiers to eat up the tumor.
