Funded by the Dick Vitale Pediatric Cancer Research Fund
Many children with bone tumors cannot be cured. This is true in particular if the tumor has come back. We are interested in using the immune system to fight cancer. In our approach, we take immune cells from patients and train them in the laboratory to fight cancer. Our training methods consists of inserting a gene into immune cells that are called T-cells. Once the cells have completed training in the laboratory, they are given back to patients. We have conducted this successfully in patients, and now want to improve our approach. Out approach consists of inserting a second gene into T-cells so that the T-cells can grow better in patients after infusion. In our proposal we now want to figure out the best structure of the second gene. We will perform laboratory studies with the T-cells we have made to determine which one works best. Once we have completed these studies, we will then proceed to develop a clinical study. The goal is to have the clinical study open for treatment at the conclusion of the grant. In the clinical study we will determine the safety of T-cells and their ability to destroy tumors. While we focus here on bone tumors, our approach could be adapted to other tumors for which immunotherapies are being developed. If successful, we hope that our approach will lead to better outcomes for children, who can currently not be cured of their cancer.
Funded by the Dick Vitale Pediatric Cancer Research Fund
Most children who die from cancer have had either leukemia (blood cancer) or medulloblastoma (brain cancer). These two types of cancer cause children to be really sick. Dr. Mullighan studies how genes cause the most common form of leukemia. Dr. Roussel studies how the brain cancer medulloblastoma grows in the brains of children. Both Dr. Mullighan and Dr. Roussel want to develop new drugs that are better at destroying cancer cells. Their idea is to develop new medicines that will have fewer side effects than the medicines that are being used today. They have discovered a new method called molecular glues to create new cancer medicines. The doctors have found that one molecular glue called SJ42872 kills both blood and brain cancer cells. They have already shown that SJ42872 kills these cancer cells in mice. They now want to find out how SJ42872 works in so many different types of blood and brain cancers. Dr. Mullighan and Dr. Roussel already know that SJ42678 works inside the cancer cells by destroying a protein call PPIL4. By doing this research, the doctors want to understand why SJ42872 is so good at destroying this protein. Then they could learn how to use SJ42872 along with other cancer medicines to kill larger numbers of cancer cells. The research will also help them understand which children will benefit from using SJ42872 as part of their treatment.
The immune system normally protects us from cancer by finding and removing abnormal cells before they grow. Many solid tumors develop when they learn how to hide from the immune system. Frequently, immune cells cannot enter the tumor because the tumor builds a strong barrier around itself. A major part of this barrier comes from a signal called TGF-beta. Tumors use proteins called integrins as “on-switches” that turn on TGF-beta. When TGF-beta is active, it creates conditions that keep immune cells out. If we can safely turn off this switch inside the tumor, the immune system may be able to enter and attack the cancer. Our research develops very small and stable proteins called lasso peptides that are designed to turn off this TGF-beta switch in tumors. By blocking the switch, these lasso peptides may open the door for immune cells to enter and may help existing drugs work better to kill the cancer cells. We will test these new agents in models of solid tumors to see how they change the tumor environment and support immune responses.We are also creating an imaging tool that lets doctors see whether the drug appropriately reaches a patient’s tumor. This information will guide future clinical studies and help match patients with the right treatment. If successful, this work will make immunotherapy effective for many more people with solid tumors and give patients a better chance at longer and healthier lives.
Funded by the Stuart Scott Memorial Cancer Research Fund with support from Hockey Fights Cancer powered by the V Foundation by AstraZeneca
Prostate cancer risk runs in families. A man’s risk of prostate cancer roughly doubles for every close family member who has been affected. Men in the family also tend to share how aggressive the cancer is. For example, how long a father survives with the cancer is strongly predictive of a how long a son will survive with the cancer. Studies have uncovered genetic risk factors for prostate cancer that distinguish which men are at high risk. But these factors poorly predict disease course. Two separate features of a cancer predict how aggressive it will be. These are 1) how abnormal the cancer cells are and 2) extent of cancer spread. Using such clinical features, two-thirds of cases are thought to be less aggressive and follow a watch-and-wait strategy. But over half advance and require active treatment. Ability to better recognize the path that the cancer is likely to take is needed. This is a study to discover the factors passed down in families that guide this path. The study also tests whether these factors predict which men followed by watch-and-wait will advance and require treatment.
Funded by the Dick Vitale Pediatric Cancer Research Fund
My group investigates specific features of pediatric bone tumors that allow them to survive. One cancer we are interested in is Ewing sarcoma. Ewing sarcoma is a common bone tumor in children. It is challenging to treat, particularly when the cancer has spread. We have become interested in a protein that is important for Ewing sarcoma cells. We want to understand what this protein does in cells. This will help us to kill Ewing sarcoma cells. We are also working with chemists to make new drugs to disrupt its activity. We will test these in Ewing sarcoma cells. Our hope is that these studies will eventually lead to new treatments for Ewing sarcoma.
Funded by the V Foundation Sonoma Epicurean in honor of Dustin and Johanna Valette
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
Asparaginase is an important drug for the treatment of childhood leukemias. However, some leukemias become resistant to asparaginase, and this makes them very difficult to treat successfully. We discovered that by blocking a protein called GSK3α, we can make drug-resistant leukemia cells sensitive to asparaginase again. Although this finding is promising in the lab, there are currently no drugs known to block GSK3α that can be used to treat patients.
This proposal is focused on overcoming this problem by testing two different but related ideas. First, we will test the hypothesis that some existing drugs, which have already been developed for other purposes, also possess the ability to block GSK3α. Because these drugs are already approved for use in patients, we would be able to quickly start testing these in patients with leukemia. Second, we have engineered several new compounds that are specifically designed to target GSK3α. Fortunately, these have shown early promise in the lab, and we are ready to evaluate whether these newly engineered compounds fit the criteria as candidates for new drug development. If this line of research is successful, we expect it will lead to two different treatment strategies combining asparaginase with a drug that blocks GSK3α.
With support from the V Foundation for Cancer Research, we are optimistic that our work has the potential to lead to the development of potent new treatment strategies for some of the most difficult-to-treat forms of childhood leukemia.
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.
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