Our bodies are constantly exposed to a multitude of challenges, such as microbes, toxins, and injuries, especially at barrier surfaces like the skin, lungs, and intestines. These tissues serve vital and complex functions in shielding us from environmental threats while also managing body moisture, oxygen levels, and nutrient absorption. For instance, the intestine must delicately balance the elimination of harmful microbes and toxins with the absorption of essential nutrients. This requires intricate cooperation between the intestinal lining cells and the intestinal immune system. Barrier tissues, like the intestine, are particularly prone to inflammation and cancer.
Inflammatory bowel diseases are chronic inflammatory conditions affecting the intestines. They result from an interplay of genetic and environmental factors, leading to dysregulated functioning of intestinal cells and immune system. These incurable diseases can significantly increase the risk of developing colon and rectal cancer. Yet, the mechanisms through which environmental factors and inflammation impact the immune system and cells of the intestine to drive the progression of chronic inflammatory diseases and cancer remain largely unknown.
Within the Niec lab, innovative tools have been developed to investigate how immune cells and the intestinal barrier cells respond to environmental challenges and interact in disease. Through this project, we aim to unravel the alterations occurring in the immune system and the intestine during inflammation. By understanding these processes, we aspire to develop strategies to prevent and treat cancer that arises from inflammatory bowel disease.
Cancer must change its nutrient uptake to grow. Drugs blocking cancer’s use of nutrients have been the basis of cancer therapy. However, most of these drugs work by blocking the pathways that metabolites use. They exhibit significant toxicity since they also harm normal tissues. We are looking at metabolite-targeted therapies that are less toxic. We hope the therapy will be more specific and effective as well. We don’t seek to block metabolite pathways. Instead, we target the specific metabolites that change in the tumor microenvironment. We study and harness the power of our body’s metabolites as drugs. Our work has the potential to change how we target cancer, leading to less toxic and more effective drugs. Our work will also help to diagnose cancer.
To understand how genes change in cancer, our field has uncovered many gene mutations and deletions in patient tumors. However, we have not yet been able to create treatments that can combat many of these changes. This research proposal will test the potential for new combinations of medicines to treat tumors with a common gene many cancers need on for survival, PRMT5. A number of aggressive tumor types have PRMT5 as a drug target including lung cancer which remains the leading cause of cancer-related deaths in the U.S. and pancreatic cancer where >90% of patients with this disease will succumb to it. We need to make better medicines to treat these cancers.
We will test our ability to drug PRMT5 protein in lung tumors in combination with other new drug targets. This work will provide fundamental insights into mechanisms of PRMT5 function and reveal new strategies to treat an aggressive and deadly form of cancer. It is necessary that we test and design effective, rationale combination therapies in cancer. These efforts aim to effectively kill tumors and to avoid tumors coming back in the patient.
This work could lead to clinical trials in the future that would directly benefit cancer patients and their families. My goal is for our laboratory to contribute to mentoring young scientists and to improving cancer treatment for patients. This V scholar award will help me to achieve my goals by providing additional support, mentorship, and scientific exchanges.
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 with support from Hockey Fights Cancer powered by the V Foundation presented by AstraZeneca
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.
