Funded by Mark and Cindy Pentecost in memory of Will DeGregorio
Ewing sarcoma relies on decades-old chemotherapy options, where aggressive treatments are met with poor disease outcomes. Ewing sarcoma is a devastating disease that affects mostly young adults age 10-16, but children under the age 10 can also develop this deadly illness. Due to the disease’s classification as a rare disease (less than 10,000 cases/year), it has not received the attention of the research community like other more common cancers; therefore, it is in desperate need of intense research and development of new therapeutic options. One of the key observations of Ewing sarcoma made back in the 1930’s is the accumulation of large amount of glycogen. Glycogen is a sugar molecule that our body uses to store energy; only specific organs such as the liver and muscle are capable of producing glycogen. The ability of Ewing sarcoma tumors to store large amount of glycogen has been forgotten until now. This proposal aims to understand the reason behind large glycogen accumulation in Ewing sarcoma and exploit the glycogen deposits as a possible drug target for the treatment of Ewing sarcoma.Dr. Sun has established ongoing collaborations with pediatric physicians to study the basis of glycogen targeting agents for the treatment of Ewing’s sarcoma, and to define early diagnostic biomarkersand evaluation of response to therapy.The long-term goal is to establish treatment options using one or multiple modalities as tailored therapies against Ewing’s sarcoma’s metabolic vulnerability.
Volunteer Grant funded by the V Foundation Wine Celebration in honor of Robert and Gail Sims
The advent of immunotherapy has dramatically changed the landscape of cancer treatments. The power of immunotherapy its potential toinduce long-lasting benefits for terminally ill patients, however only a minority of patients are currently responding to the treatment. We have previously shown that the composition of the immune cells found within the tumor is critically important for the therapeutic outcome, with two immune cell types being required for a strong and effective tumor elimination. These cell types are so-called killer T-cells, which recognize and eliminate tumor cells and dendritic cells, which are needed to “license” T cells to kill.
Killer T-cells are most effective when they are directed against targets only present on tumor cells and when all tumor cells have an evenly distributed expression of this target. However, in most tumors the targets are unevenly represented and only partially present representing ahurdle for successful tumor cell elimination. But more importantly this diffuse pattern directly weakens the strength of the killer T-cellresponse and changes the composition of immune cells in the tumor. To date we do not understand why a weaker T-cell response is observed and how we could overcome this shortcoming therapeutically. In the funded study, we aim to understand the dynamics of akiller T-cell responses against tumors with uneven target expression. In doing so we aim to understand which factors impact the expansion and function of killer T-cells and ultimately harness this knowledge to expand the fraction of patients benefiting from immunotherapy.
Funded through the Stuart Scott Memorial Cancer Research Fund by the Ayodele family in memory of Ade Ayodele
Colorectal cancer (CRC) is preventable when detected early. Because of effective screening, fewer Americans aged 50 and older are now being diagnosed with CRC or dying from it. Over the past 20 years, however, the number of Americans under age 50 who are diagnosed with CRC has doubled. Health experts estimate that the numbers of younger Americans with CRC will continue to increase rapidly over the next 10 years. The reasons for this increase are poorly understood. In addition, younger people are less likely to be diagnosed with CRC when the disease is still at an early stage. Also, of concern is that among men and women of all ages and all races, African-American men are the most likely to die of CRC.
The goal of this study is to better understand the reasons why people under age 50 in Utah are being diagnosed with CRC. As a first step, the researchers plan to identify the specific places in Utah where diagnoses of CRC among younger people are increasing the most. Next, they plan to conduct 1-hour recorded Zoom interviews over phone and/or video with 20 people who live in these places and were diagnosed with CRC when they were under age 50. Thirdly, the researchers plan to create and test a program that will raise Utahns’ awareness of the increasing risk of CRC among residents of the state who are aged under 50. This study is unique as CRC survivors are key to helping drive the study forward.
Funded through the Stuart Scott Memorial Cancer Research Fund by the Marks Family in honor of Lisa Curtis
The human body is estimated to remove over a billion cells every day, a process achieved by a relatively rare population of cells called phagocytes. When a phagocyte ingests a dying cell, it essentially doubles its content (analogous to a neighbor moving into your house). Yet, phagocytes such as macrophages often ingest multiple targets in quick succession. How these phagocytes maintain their homeostasis and manage the excess influx of dead cell cargo, are interesting scientific problems that are largely unexplored. This is an important topic in understanding cancer development broadly, and the development of cancer therapies specifically, because the clearance of cancer cells directly establishes an environment for the tumor to grow. Exciting avenues of therapy involve trying to either break down this tumor-promoting environment or by increasing the immune response against the tumor. These approaches show much promise; however, they often only work in specific patient populations. We believe that to develop a more effective therapy, we must understand the underlying processes that link clearance of cancer cells to generating an anti-cancer immune response. To this end, my lab focuses on studying phagocytes that are prevalent in Triple-Negative Breast Cancer (TNBC), how tumor cell clearance contributes to TNBC progression, and discovering new ways to target these cells to treat TNBC.
Funded by the Constellation Gold Network Distributors
Non-Hodgkin Lymphomas are common cancers which can be cured in some patients by combinations of multiple chemotherapy drugs. Currently, these treatments consist of giving many drugs at the same time, waiting some weeks to recover from side effects, and repeating the cycle several times. We have discovered that in the most common combination therapy for Non-Hodgkin Lymphomas, while the use of many chemotherapies kills more cancer cells, the drugs do not enhance one another’s activity. Instead, certain drug pairs interfere with one another’s effects. This suggests that treatment might be more effective at killing cancer cells, and cure more patients, if this interference were avoided. This could be accomplished by giving certain chemotherapies at different times from each other. We will study a few lymphomas and measure how chemotherapies interact to determine which should or should not be given at the same time. A computer model will simulate how tumors respond to combinations of drugs given at various times. This simulation will use measured drug interactions to predict which treatment designs will be most effective at killing cancer cells. We will test these treatments on human lymphoma cells, and compare them to the current ‘all-drugs-at-once’ strategy. If this research finds a more effective approach to treatment, it can next be tested in animals, and eventually in human clinical trials. Ultimately we hope to identify a simple change in the use of already approved medicines that has the potential to cure more cases oflymphoma.
In the last three decades, no new drugs that can effectively treat pancreatic cancer have been found. One of the major problems in pancreatic cancer is that most research is performed on patients where the cancer has not spread to the rest of the body. This is because these patients are eligible for surgery and researchers have access to the tissue for experiments. However, most patients with pancreatic cancer are diagnosed when the disease has already spread. Patients where the disease has spread do very poorly compared to patients where the disease has not spread. We believe that there are changes in the cancer’s DNA that cause the disease to spread.
To investigate this, our laboratory compared the DNA from patients where the disease had or had not spread, and found that a gene that can potentially promote the spread of this cancer. This gene, named KRAS, multiplies inpatients where the cancer has spread. Patients where this gene has multiplied are very resistant drugs used to treat this cancer. The goal of our project is to understand how the multiplication of this gene is related to therapy resistance. Using specialized techniques in our laboratory, we will grow tumor cells from patients with and without multiple copies of KRAS to figure out changes in the cell that are related to this specific genetic change. We intend to use this information to find new drugs to treat patients where the cancer has already spread.
Funded by the Hirsch Family in memory of Ann Hirsch
There is a strong need for new treatments for brain tumor patients. To address this need, we asked how a common mutation in brain tumors may create weaknesses that we could use to develop new treatments. We identified a process that brain tumor cells with this common mutation rely on to live. Next, we used a drug to block this process and found that it kills brain tumor cells with this common mutation. We would like to know why these cells rely on this process and whether brain tumors grown in mice respond to this drug. If our work is successful, our efforts could lead to new studies that will test this drug in human brain tumor patients. We are hopeful that our discovery could lead to improvements in the lives of brain tumor patients.
Funded by the Constellation Gold Network Distributors in honor of the Dick Vitale Fund
Leukemia is the most common cancer among children in the US. It is also the leadingcause of death from cancer before 20 years of age. Despite advances in diagnosis and treatment, a subset of leukemias affecting infants predict poor outcomes. Leukemic cells in these patients carry a fusion gene known as MLL rearrangement (MLL-r). MLL-r is critical for the development of leukemia cells, and has been well studied over the years. However, current therapies targeting MLL-r showed modest clinical activity. Therefore, there is a need of finding additional drug targets. We have found a previously unknown protein complex required for the survival of MLL-r leukemic cells. In this project, we propose to test if blockingthis complexdelay the growth of MLL-r leukemia in cells and animals. We will also investigate the molecular mechanisms behind. Taken together, our work will provide preclinical evidencefor a new protein complex as a potential target for MLL-r leukemias. More broadly, our technologies will help the study of other childhood cancers.
Funded by the Constellation Gold Network Distributors in honor of the Dick Vitale Fund
Alveolar rhabdomyosarcoma (ARMS) is an aggressive cancer of the muscle that occurs in young children and teenagers. Despite years of attempts to improve chemotherapy regimens, survival of patients with ARMS remains poor. Thisisespecially true for patientswho have advanced disease at the time of diagnosis. ARMS tumors typically possess a single and defining genetic mutation.Abreak in one specific chromosome will fuse with another chromosome, creating a fusion gene. These fusion genescan control hundreds or even thousands of other genes and transform a normal cell into a cancer cell. My project focuses on the PAX3-FOXO1 fusion. This fusion causes the most severe form of ARMS. However,there are no therapies that target PAX3-FOXO1 directly. Our goal is to understand how PAX3-FOXO1 transforms a normal cell into a cancer cell so that we canfind new and precise therapies. To study this, we use zebrafish as a disease model because they are genetically similar to humans. We will integratethe human PAX3-FOXO1 fusion geneinto the zebrafish genome to determine the stepsrequired for ARMS tumor formation. For example, often normal development is hijacked by cancer genes. Our studies will determine if and how this happens in ARMS. Directly comparing zebrafish and human ARMSwill pinpoint the most important drivers of disease and likely find new options for more targeted and specific therapies.
Melanoma is an aggressive form of skin cancer that frequently spreads (metastasizes) to other organs. While some patients with metastatic melanoma benefit from novel drug therapies, such as immunotherapies, which reinvigorate the body’s own immune system to detect and eliminate cancer cells, most patients do not. Interestingly, patients who have metastasis to the liver are significantly less likely to respond to immunotherapies, and the underlying reasons are unclear. Here, we established a melanoma mouse model that, similar to patients, experiences liver metastasis, and therefore enabling us to study the impact of these lesions on responses to immunotherapies. We use cutting-edge methods, such as genome-editing tools and high-resolution molecular profiling and imaging methods to dissect both how liver metastases develop and how they impact the immune system in the entire body. The ultimate goal of this work is to develop improved therapies for melanoma patients with metastases to the liver.
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