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.
Lung cancer is a deadly disease. This lethality is due, at least in part, to how often and how extensively these cells can spread throughout the body. My laboratory is working to understand what causes these cancer cells to spread and how they survive this process. By doing so, we hope to identify new ways to treat lung cancer.
We are interested in the nutrients cancer cells use to support growth and how these nutrients might help cancer cells spread. We are particularly interested in fats, or fatty acids. These complex nutrients play many different roles in cells, including helping to maintain cell structure, storing energy, and even acting as a method of communication with other cells. When we measured fatty acids in lung cancer, we saw that several fats and fatty acid pathways were different in tumors that spread throughout the body, compared to tumors that did not. In this study, we investigate how fatty acid metabolism supports aggressive cancer cells, and we will test whether blocking these fatty acid pathways can prevent lung cancer cells from spreading.
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 the Dick Vitale Pediatric Cancer Research Fund
Osteosarcoma (OS) is a cancer of the bones that affects up to 500 children, teens, and young adults each year. While current therapies are effective for many patients, patients that have multiple tumors or have tumors that do not respond to chemotherapy have poor outcomes. CAR T cells are a therapy that uses the immune system to fight cancer. CAR T cells have been successful in patients with blood cancers that no longer respond to chemotherapy but CAR T cells have had limited success in solid tumors. My lab has developed a new form of CAR T cells that are more potent and last longer in the body. This project will explore whether our new CAR T cells can work against OS. OS is a common cancer in dogs and OS in dogs is very similar to OS in children. The Flint Animal Cancer Center is internationally recognized for running cutting edge clinical trials for dogs with cancer. This project will test our new CAR T cells in pet dogs that have OS and are in need of advanced therapies. Since OS is very similar between dogs and children, making a therapy that is effective in dogs will produce valuable data for developing a clinical trial for children with untreatable OS.
Funded by the Dick Vitale Pediatric Cancer Research Fund
The most common cancer in children, including teenagers, is a blood cancer named leukemia. Chemotherapy is the main treatment for pediatric leukemias. Although most patients respond well, some do not, leading to poor outcomes. Chemotherapy can also have negative side effects both during treatment and for the rest of their lives.
Patients who don’t get better with chemotherapy are those that have one of most common genetic changes, the rearrangement of a gene called KMT2A (KMT2A-r). In a study at The University of Texas MD Anderson Cancer Center, patients with KMT2A-r leukemia survived for 6 months after 2 chemotherapy treatments and only 2.4 months after 3 or more treatments. Scientists are looking at new ways to treat these patients and help them live longer.
Menin inhibitors could be a good option because they target KMT2A-r leukemia and have fewer side effects than chemotherapy. But some patients with KMT2A-r leukemia can also have mutations in other proteins that don’t let the menin inhibitors work as well by themselves.
With the help of the V Foundation, Drs. Andreeff, Carter and, Cuglievan, at MD Anderson Cancer Center plan to test different combination treatments that target menin and other proteins at the same time to get better results. This can potentially help children with KMT2A-r leukemia live longer and have better lives.
Funded by the Dick Vitale Pediatric Cancer Research Fund
Malignant rhabdoid tumors and epithelioid sarcomas are rare cancers that can develop throughout the body. Sadly, these tumors are often deadly for patients who can’t have surgery or whose tumors don’t respond to chemotherapy. Recently, a new drug called tazemetostat has been approved to treat these cancers, but only about 15% of patients get better with it. Our new research project explores DNA damage repair and targeting its mediators in tumors cells to offer new treatments to patients. Our past research shows that a protein called ATR is important for the growth of tumor cells. It is possible that other similar proteins are necessary for tumor growth and is therefore important that we study them to understand if ES and MRT patients may benefit from other drugs that interfere with these processes. For example, we found that combinations of drugs, chosen logically based on research evidence, is more effective in controlling tumor cell expansion, when compared to using drugs alone. We plan to find the best combination of novel drug inhibitors to stop these tumors from growing. We also want to understand how these drugs work in the body so we can predict which patients will benefit the most. This research should lead to a new, safe, and effective treatment for many patients with RT and ES who currently have no cure. The findings might also help treat other types of childhood and young adult cancers, creating a roadmap for difficult to treat tumors.
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.
