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 with support from Hockey Fights Cancer and Jeffrey Vinik
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.
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 with support from Hockey Fights Cancer and Jeffrey Vinik
Diffuse midline glioma (DMG) is a very aggressive brain tumor that occurs mostly in children. DMG treatment involves surgery, radiation, and chemotherapy, but most people with DMG don’t live longer than a year despite these treatments. We desperately need better therapies for this disease. Treating DMG is difficult because tumors aren’t the same in every person, so a drug that works for one person might not work for another. Therefore, we need treatments that are personalized for each patient. In addition, different parts of the tumor may not all respond to the same drugs, and we might need to use a mixture of drugs to eliminate the whole tumor. And even if we find drugs that do this in the lab, getting them into the tumor is tricky because of the “blood-brain barrier”, which prevents many drugs from getting from the bloodstream into the brain. We are proposing a new approach to DMG treatment that overcomes these challenges. To find individualized treatments, we will test many different drugs on tissue from surgery or biopsy to see which ones work best for each patient. We’ll also look at the effects of drugs on individual cells in the tumor and find the combinations of drugs that kill the most tumor cells. Finally, we’ll use a method called convection enhanced delivery (CED) to pump drugs directly into the tumor, bypassing the blood-brain barrier. By using these approaches, we will find better treatments for DMG and other brain tumors in kids.
