Cancer treatments often fail to produce durable responses and resistant tumors eventually regrow. This process presents a major clinical challenge and results in significant patient mortality. The molecular details of this process, termed acquired resistance,are poorly understood and there are currently no therapeutic options to prevent it. For cancer immunotherapy, acquired resistance is emerging as a prevalent phenomenon affecting approximately half of patients who initially respond to treatment. Key to this process are the leftover tumor cells which remain alive and seed resistant tumors. We have observed a small subpopulation of cancer cells which survive directcytotoxic T cell attack over prolonged time periods. These cells, termed persister cells, survive through unknown mechanisms. In this proposal we will determine how persister cells survive despite undergoing T cell attackand also how a subset of persister cells eventually regrow and exhibit overt T cell resistance. If successful, our proposed work will shed light on acquired resistance to immunotherapy and may reveal new approaches to prevent tumors from recurring.
Pancreatic cancer will soon become the second biggest cause of death from cancer in the United States. Patients usually find out they have this disease after it is too late for surgery. This leaves treatment as the only option, and the ones in use only help patients live for a few months. To change this, we need to find new approaches to improve the survival of our patients.
Pancreatic cancer is hard to treat for many reasons. A key issue is that the tumors are made up of many cell types, not just cancer cells. Over the past few years, we have found ways these different cells can act together within a tumor to help cancers grow or avoid therapy. Most recently, we discovered that cancer growth can be slowed by blocking exchange of the amino acid asparagine when their mitochondria are stressed.
The goal of this project is to show how cancer cells make and share asparagine. Knowing this, we can better target this metabolism to kill the cancer cells. From our previous work, we also predict this strategy will help patients better respond to immunotherapy. The results from this project will show us how to improve pancreatic cancer treatment and provide data we need to start new clinical trials.
Funded by Matthew Ishbia and the Dick Vitale Pediatric Cancer Research Fund
DNA contains the story book of each human, written in our genome. Sometimes a single letter changes the meaning of a word, such as better to bitter. Likewise, in some children a small DNA change encourages cancer to form and grow. In childhood sarcoma, we recently discovered that certain DNA changes in cancer-causing proteins lead to errors in the rest of the genome’s ability to remember its cellular purpose. We found this was happening by formation of large “super-clusters” at cancer-causing genes. The goal of our research is to discover why and how these super-clusters form. We will explore the super-clusters using leading edge technologies including 3-dimensional genomic modeling, chemistry, cancer biology, and drug development focused on a deadly form of childhood cancer, called rhabdomyosarcoma. We anticipate finding that the super-clusters are integral to rhabdomyosarcoma progression; and our work will illuminate potential new treatment targets and routes, based on modifying the genetic error that is causing the cancer. For example, if we develop drugs that stop the formation of the super-clusters, will we also selectively kill the cancer cells? This new work will provide the scientific data to support a new class of therapies for children with these deadly cancers.
The immune system is our body’s defense against cancer and other threats. Recently developed drugs enable a patient’s immune system to attack cancer and potentially destroy it. These drugsthat enlist the immune system have revolutionized cancer treatment. However, despitesuccesses, not all patients respond to these exciting new drugs. Cancers that do not respond tothese drugs are known as “cold” tumors because they prevent an attack by immune cells. Thisbreakdown occurs because many cell types must communicate effectively with one another foran immune response against cancer to occur – cancer disrupts this process. We will test whetherimmune cells can be improved, such that they are resistant to the miscommunication that cancercauses. Normally, immune cells use signals to communicate with each other. Cancer eitherblocks these signals or replaces them with ones that are misleading. Our goal is to restore thesignals needed by immune cells so that they can mount an effective and sustained attack againstcancer. To realize this goal we have developed activators of these signals. We will determinewhich of these signal activators can protect immune cells from being misled or disabled bycancer. Our long-term goal is to improve cancer treatment options by developing these signalactivators into new therapies that allow a patient’s immune cells to attack a cold tumor.
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.
While Helicobacter pylori is the major risk factor for development of stomach cancer, only 1-2% of those infected with H. pylori get gastric cancer suggesting the existence of additional necessary factors. We hypothesize the oral bacterium Fusobacterium nucleatum, which normally does not colonize the stomach, can colonized the altered tissue environment created by H. pylori infection to further drive tumor progression. Testing this hypothesis will yield new insight into the mechanisms of bacterial carcinogenesis and highlight new opportunities for intervention.
Our lab is developing treatments for human cancers by engineering immune cells called “T cells” to recognize and kill tumor cells. Engineered T cells can eradicate tumors in patients with blood cancers, like leukemia and lymphoma. However, they have had limited success so far against more common “solid tumors”, like breast and lung cancer, which are responsible for the majority of cancer deaths. Solid tumors can evade attack by inducing T cells to lose function and become “exhausted.” Strategies to preserve T cell function, thus, are needed to extend the success of engineered T cell therapy to solid tumors. Our lab has developed a mouse model of lung cancer that mimics human tumor development and patient response to therapy. In this model, T cells engineered to overexpress a gene that promotes T cell function dramatically eliminated tumors in ~50% of mice. Based partly on these results, a clinical trial is being planned to test whether these T cells are safe and effective in patients. However, our data show that tumors still progress in ~50% of mice. We will use the mouse model we developed to define why tumors progress in a subset of mice and test different combination treatments to identify regimens that improve T cell function and kill tumors most effectively. Working with Fred Hutch clinicians and industry partners, our goal is to translate the strategies that appear most effective in mouse models to the clinic to test their impact in patients.
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 by Matthew Ishbia and the Dick Vitale Pediatric Cancer Research Fund
Childhood cancers of developing muscle are some of the most difficult to treat childhood cancers. Therapy has not significantly changed in the past 20 years and there isn’t even a meaningful new treatment being considered. Currently, even after the most intensive therapy possible, a third of these tumors will return and take the life of a child or young adult. We have taken a new approach using state-of-the-art methods to identify what we hope will be more targeted and less toxic treatments that yield better outcomes. We have already identified three new therapeutic avenues that we will test. The first is to ask if the abnormal gene that drives this disease, called PAX3-FOXO1, is a good drug target. We engineered the gene to be sensitive to a derivative of a known drug. While we can’t do this in kids, it allows us to ask what would happen if we had a drug? Second, we found that PAX3-FOXO1 turns on a small number of other genes, and we already have drugs that can target some of these. Third, we identified other possible drug targets that PAX3-FOXO1 recruits. We will test if these are key to causing cancer and if they would be good drug targets. We believe that our comprehensive approach gives us the best chance in the past 30 years to change the lives of these children with cancer, and to identify drugs or drug combinations that will be less toxic and yield better outcomes for these patients.
Funded by the Stuart Scott Memorial Cancer Research Fund
We believe that the immune system in patients witha precursor condition to multiple myeloma (a cancer in the bone marrow) allows the disease to progress (worsen) into more serious disease. Our project aims to find immune biomarkers that predict disease progression and identify patients who will likely progress early to treat the most at-risk patients before they become symptomatic. These markers may include changes in the number or type of immune cells or changes in the way those cells work. We will also examine how patients’ immune systems change in response to a new treatment that targets immune cells. We will use DNA and RNA sequencing and spatial imaging to investigate single cells from the bone marrow. We will gain a detailed picture of how the immune system supports or fights the tumor. This work will support the development of new treatments that may slow or stop disease progression.
