Funded by the Dick Vitale Pediatric Cancer Research Fund with support from the Rudd Foundation in memory of Leslie Rudd
Immunotherapy is a type of cancer treatment that boosts the body’s immune system so that it can fight the cancer. Whilst this type of treatment has proven very successful for certain cancers in adult patients, this approach has been much less effective for the treatment of cancer in children. One reason for this is that the immune system of children is very different from adults and may not respond to treatments designed to target adult immune cells. Remarkably little is known about the cell types in children that suppress anti-cancer immune responses. The Brown Lab recently discovered a new type of immune cell —Thetis cells — that may be pivotal in reducing the efficacy of immunotherapy in the very young. We hypothesize that Thetis cells help to “train” T cells not to attack the body’s own normal cells, and in so doing creates an immune environment that also tolerates malignant tumors. In this project, the Brown Lab seeks to reveal, on the molecular level, how Thetis cells work and thus how to create immune therapies for children while not provoking auto-immune diseases that overactive T cells sometimes cause.
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.
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.
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.
Immune checkpoint blockade (ICB) is one type of immunotherapy that has been FDA-approved for thetreatment of melanoma, bladder cancer, lung cancer, and other cancers. For some patients, ICB canlead to dramatic shrinkage of their tumors and extend their life. However, many patients do not see thisbenefit and some patients develop serious side effects. For most cancer patients, there is no way topredict if they will benefit from or be hurt by ICB.A test that could give doctors and patients a better understanding of the risks and benefits for ICBtreatment for each individual is urgently needed.Examining the blood of patients, we discovered certain immune cells in patients who are less likely tobenefit from ICB. We have found this is true for both melanoma and bladder cancer patients. We plan to examine whether these cells also matter for patients with other cancers and if there are differences in these immune cells depending upon a patient’s race. We also would like to better understand thisspecial population of immune cells and how they may be linked to immune cells in the tumor. We hopethat this will lead to the development of a safe and easy test that will provide patients betterinformation about how ICB treatment will work for them. With this information, we hope to allowpatients to feel and function better and live longer by finding a therapy that will be more likely tohelp and less likely to hurt them.
Funded by the Dick Vitale Pediatric Cancer Research Fund
We aim to develop a novel and effective therapy for a lethal pediatric brain cancer (diffuse midline glioma, DMG). No effective treatment for DMG currently exists. This cancer arises when a mutation appears in a gene called H3F3A, causing it to produce a toxic protein. The mutant protein makes cells grow unchecked, forming a tumor in an inaccessible brain region and eventually killing the patient. Each of our genes makes RNA—so-called messenger RNA (mRNA)—and the mRNA is then read in another part of the cell to make the protein encoded by that gene. The technology we use, called “antisense”, allows us to target the mRNA made from a gene, and either destroy it or change it. Either way, the toxic protein is no longer made, and because the tumor cells require it for growth, they stop growing and die or change into normal cells. Once our antisense drug is developed, it will be injected into the fluid surrounding the spinal cord, allowing it to reach the brain tumor. Another gene, called H3F3B, encodes the same protein as H3F3A, so our method will get rid of the defective protein but not the normal protein. Therefore, the drug should not harm normal tissues outside the tumor. We will design, test, and perfect our antisense approach using cells derived from DMG tumors, and mouse models of this brain cancer. If this project is successful, the resulting antisense drug will undergo further safety tests, in preparation for clinical trials involving DMG patients.
Funded by the Wine Celebration in honor of Carol Bornstein
Tumors are constantly growing and mutating – they are different from healthy cells, and thus should be able to be recognized by your immune system. However, immune cells respond to molecules that act as brakes, which can be used by tumor cells to escape being killed. While some of these immune brakes have been discovered, drugs blocking these do not work in most cancer patients, and many remain unknown. To improve survival for everyone, we need to figure out what the other important brakes are so we can reprogram your own immune system to fight cancer. We have recently discovered Siglec-15 as a new immune cell brake in tumors.Blocking Siglec-15 shows improved immune activity in studies involving human cells and mice. Based on these results, clinical trials targeting Siglec-15 are currently ongoing. Initial trial results show that targeting Siglec-15 is safe and slows down tumor growth in patients who have already failed other therapies. Thus, we need to understand the biology of Siglec-15 so we can design the best cancer therapy possible. Here, we will study how Siglec-15 suppresses tumor immunityand identify strategies to maximize its clinical response. Our proposal will improve our knowledge of cancer immunology and help patients in the fight against late-stage cancers.
Gastric cancer develops in the setting of chronic inflammation that both promotes cancer progression and that also blocks the body’s immune response which otherwise might restrain tumor growth. Chronic inflammation comprises a number of different types of white blood cells, but one type, called “myeloid derived suppressor cells”, plays an important role in blocking T lymphocytes, the main immune cell that protects us against cancer. We have shown in several mouse models that “myeloid suppressors” expand in gastric cancer and mediate some of the resistance to the newest immune therapies (called immune checkpoint inhibitors such as anti-PD1 drugs). We are proposing to study the importance of these myeloid suppressor cells further using several different mouse models and also analysis of human gastric cancer tissues. We will be testing a novel peptide shown by our lab to inhibit the expansion of myeloid suppressors, and also a small molecule that we have shown can inhibit the production of these cells in the bone marrow. Overall, our goal is to advance new therapies to target inflammatory cells that resistance to immune therapies in cancer.
Previously, the main treatments for cancer patients were surgery, radiation, and medicines with many unpleasant side-effects. The discovery that there are ways to turn our own defense system against cancer became a medical revolution. In some patients, this new treatment led to miracle cures that had never been seen before. The discovery was so incredible, it won a Nobel prize. Unfortunately, this new treatment does not work in as many patients as we would like. It is still a mystery why two people with the same cancer will respond differently to treatment, one patient might be cured and the other patient does not get better. This project is trying to figure out ways that will help doctors know who will be cured and who will not get better with this new treatment. We are developing a blood test to predict who will be cured before treatment begins. For those patients that are not likely to be cured, we are doing experiments to develop a medicine that can be added to the treatment in order to make the treatment cure many more patients.
Funded in partnership with the Cancer Research Institute through the V Foundation’s Virginia Vine event and Wine Celebration Fund-A-Need
Glioblastoma (GBM), the most common malignant brain tumor, is one of the most aggressive forms of cancer with limited therapeutic options and a dismal prognosis. The median survival of patients is 14.6 months. A significant barrier to treatment is the immunosuppressive tumor microenvironment (TME). A cancer vaccine is a form of immunotherapy that boosts the body’s defenses to fight cancer. We have developed personalized cancer vaccines based upon patient-specific neoantigens unique to a patient’s tumor to prime and boost immunity with the long-term goal to delay or prevent a recurrence. Twelve patients have been vaccinated with a peptide-based vaccine that incorporates up to ten personalized epitopes. Our preliminary results show induction of systemic immunity and an estimated favorable 6-month progression-free survival of 90.9% and 12-month survival from surgery date of 87.5%. We detected circulating antigen-specific cells in the blood that were apparent in ex vivo assays, suggesting priming of high-level responses. We now intend to apply new technologies (spatial sequencing, mass cytometry (CyTOF), imaging mass cytometry and O-link proteomics) to analyze the TME in GBM in depth, determine cross-talk of the tumor cells with the immune cells and other brain cells hijacked by the tumor to grow, and screen for circulating immune factors and their co-stimulatory and inhibitory molecules. The cellular and molecular profile and distribution of cells in the TME and the in-depth analysis of blood cells and soluble protein biomarkers will help predict response or resistance and identify new immunotherapy targets.
