Designed to identify, retain and further the careers of talented young investigators. Provides funds directly to scientists developing their own independent laboratory research projects. These grants enable talented young scientists to establish their laboratories and gain a competitive edge necessary to earn additional funding from other sources. The V Scholars determine how to best use the funds in their research projects. The grants are $200,000, two-year commitments.
Glioblastoma (GBM) is the most frequent and deadly malignant brain tumor. Escape from the body’s immune response is a critical factor that makes GBM untreatable. One promising anti-GBM strategy is to augment the tumor-fighting capacity of immune cells. CD8+ T cells have the potential to kill tumors, but cancers make them not function properly. Strategies that aim to prevent this process have not been successful in GBM yet. We recently found that a molecule named dipeptidyl peptidase 4 (DPP-4) is present on dysfunctional T cells at high levels. Furthermore, we observed that DPP-4 prevents CD8+ T cells from killing tumors. In this application, we aim to determine how DPP-4 reprograms T cells to a nonfunctional state. DPP-4 inhibitors are commonly used by patients with diabetes. We seek to repurpose these drugs in combination with existing immune-activating strategies to improve T cell response against GBM. Collectively, these studies will define DPP-4 as a new treatment target in GBM.
Radio- and chemotherapy work by damaging the DNA of cancer cells, but malignant cancers, like glioblastoma, often regrow more resistant to therapy. Surprisingly, treated tumors don’t always have new mutations in their DNA, prompting the question: How did treatment change the tumor?
We believe that non-genetic chemical “scars” on DNA from therapy make cancer cells more aggressive. This theory is hard to study because radio- and chemotherapy cause random DNA damage. To overcome this, we developed an experimental system that creates DNA damage at precise locations, providing a clear map of the damage.
Our research shows that DNA damage leaves non-genetic changes in cancer cells’ blueprints, such as DNA methylation and changes in gene expression. We believe these non-genetic changes help cancer cells behave more aggressively and resist treatment. By understanding how these alterations occur, we aim to develop therapies that prevent cancer cells from adapting to treatment.
The immune system plays a crucial role in controlling cancer growth. Immunotherapies help fight cancer by boosting the body’s immune response against the tumor. However, many patients have tumors that either don’t respond or become resistant to these treatments. One reason for this resistance is that a type of immune cell called macrophages, which are found in the tumor, can shut down the immune response and stop it from killing cancer cells. Right now, we don’t have effective treatments to target these macrophages. Our research team has discovered a new weakness in these macrophages. By blocking a special protein they use, we can stop them from taking in folate (a type of vitamin), which leads to their death. We will use patient samples and a new mouse model we created to figure out why these macrophages need folate and how we can use this information to enhance the immune response against tumors. This could lead to new treatments that specifically kill macrophages in tumors, helping more cancer patients benefit from immunotherapy.
Our lab works on finding new and better immunotherapies for cancer. To do this, we try to understand how cancer cells hide from the immune system. We also try to understand which proteins could be targeted with a drug to help the immune system find and kill cancer cells more effectively.
To accomplish this, we are studying ancient viruses that live in the DNA of all human cells. Usually, these viruses are kept quiet by “epigenetic repressors”. Our lab is studying how to turn on these viruses in cancer cells, with the goal of activating the immune system to kill the tumor.
We envision this approach leading to a new type of cancer therapy, which could be used in patients that don’t respond to standard immunotherapies.
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
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.
