Colorectal cancer is a leading cause of cancer death in the U.S. A major challenge in the treatment of cancer in general, and colorectal cancer specifically, is the ability of cancer cells to travel throughout the body and get into other organs. This means that we need medicine that attacks the cancer anywhere in the body. Cancer cells live with other types of cells that help it survive our medicines and let the cancer move around. The focus of my research is to make the cancer more susceptible to medication and less able to move around. This grant will test a new medicine that changes the blood vessels and cells that support the cancer. We will do a clinical trial adding this new medicine to the normal ones already used to treat colorectal cancer. This research will help find new treatments but also teach us more about the cells that support cancers and how to stop them.
Colon and rectal cancers are deadly diseases. The currently used treatments can improve the survival for patients, but new options are still needed. Some patients can benefit from drugs that speed up the body’s immune system against the cancer. Unfortunately, it is not currently clear which cancer patients are most likely to benefit from these treatments. Cancers can, in many ways, act like wounds that never heal. The scar tissue that forms around cancers contains important aspects that can prevent how your body’s immune system can see the cancer as abnormal. Additionally, in some cancers there are features that can actually stimulate the immune system. By better understanding these factors, we might be better able to identify which patients are most likely to benefit from these immune treatments. Also, understanding these processes can help make better immune drug combinations that can overcome these immune inhibiting factors. In this study, we first examine how these factors within the scars around cancer cells change the ability of the immune system to detect and enter cancers. Next, we look at which factors are associated with immune treatment response. Lastly, we study new treatments that might convert immune inhibiting cancer features to ones that stimulate the immune system.
Colorectal cancer is the second most common cause of cancer death. Immunotherapy is largely not effective in this disease. To work safely, it requires targets in tumors that are not also present in normal tissue. These are difficult to find. Our recent research shows that advanced colorectal cancers adopt a fetal-like state. This fetal-like state reactivates gene programs that are normally only expressed during early development. In normal adult tissues, these programs are turned off. This may make advanced cancer vulnerable. Reactivated fetal proteins could potentially be used as targets for new immunotherapies. Here we propose to study how these fetal proteins are recognized by the immune system. For this, we will use our unique and extensive biobank of organoids. Organoids are 3D cultures of cancer cells derived directly from patient tumors and normal cells. They are a more informative and realistic model of cancer than traditional cell cultures. We must first understand which molecules are shown to the immune system in cancer cells. We will then look for immune cells in the blood of colorectal cancer patients that can recognize the fetal molecules. This approach will ultimately lead to novel immunotherapies. These could help treat advanced colorectal cancer and related solid tumors.
One of the most common kidney cancer syndromes is called HLRCC. Individuals with HLRCC are at risk for developing highly lethal kidney cancer, painful skin tumors, and fibroids. Better cancer prevention and treatment strategies are needed for HLRCC patients. HLRCC is caused by a mutation in a gene involved in metabolism. We found that the tumors that form in HLRCC patients have a unique metabolism that is reliant on the purine salvage pathway. Medicines have already been developed to block the purine salvage pathway, and one such medication, called 6MP, is currently used to treat patients with other types of cancer or autoimmune diseases. We found that HLRCC tumors are highly sensitive to 6MP treatment, and now propose to conduct a Phase 1 clinical trial to test safety and dosing of 6MP in HLRCC patients. We also propose to examine ways to prevent kidney cancer formation in HLRCC patients. This proposed research could have a huge impact on the lives of HLRCC patients through enabling clinical translation of a promising approach to treat their cancer and reveal effective cancer prevention strategies in this vulnerable patient population.
Fifty percent of people with Lynch Syndrome–related mutations will develop colon cancer. Over the last few years, we have started to understand that the immune system plays an important role in fighting colon cancer in Lynch Syndrome. The immune system is an army that protects us from cancer. In our project, we want to measure the strength of this immune army in patients that carry the Lynch mutation. We hope that these measurements will tell us who is at risk of developing cancer and minimizing the uncertainty of patients. Our goal is to study the immune system of patients that carry Lynch mutations in order to develop laboratory tests that one day can be used to predict which patients have a higher risk of developing colon cancer. At the same time, we hope that by studying a patients immune system we can understand the types of cells that are needed to fight cancer, and ways to develop new immune treatments to prevent cancer.
Brain cancers are typically fatal, even when patients undergo intensive treatment. While treatments have recently improved for many cancers, the last major treatment advance for glioblastoma (the most common aggressive brain cancer) was decades ago. Our research team is taking a new approach. We have discovered that aggressive brain cancers like glioblastoma often steal nutrients from the rest of the body. In this V Foundation-supported work, we will discover how brain cancers use these nutrients and whether blocking this nutrient uptake will slow brain cancer growth and improve treatment responses.
Multiple myeloma (MM) is a type of bone marrow (BM) cancer that remains a significant challenge to treat, despite therapy advancements. In this study, we aim to explore a new approach to enhance the effectiveness of standard MM treatments. Our focus is on a specific type of immune cells called myeloid cells, that play a role in tumor growth and immune evasion in MM patients. We observed that MM patients have an increase of a particular type of myeloid cell that express on their surface, a molecule called CXCR2, in the BM and places where the cancer has spread to bone: (osteolytic lesions). The myeloid cells may contribute to MM resistance to treatment and to evasion of the body’s immune system. Based on these findings, we propose a clinical trial to test a drug called SX-682, which targets CXCR2-positive myeloid cells. We will investigate whether adding SX-682 to standard MM treatment will improve patient outcomes. Our trial will focus on MM patients whose cancer has come back after initial treatment. The primary goal of our study is to assess the safety and tolerability of SX-682 with standard MM treatment. Additionally, we aim to understand how SX-682 affects the immune environment within the tumor and in the blood. By targeting CXCR2-positive myeloid cells, we hope to enhance the body’s ability to fight MM, improving patient survival. Our study represents a promising step towards developing more effective therapies for MM by harnessing the body’s immune system to better combat this challenging cancer.
Funded in partnership with WWE in honor of Connor’s Cure
Pediatric Diffuse Midline Gliomas (DMGs) and High-grade gliomas (HGGs) are aggressive brain tumors. Unfortunately, current treatments don’t work well for these tumors. Our research shows that energy pathways play a role in making these tumors resistant to treatment. Specifically, proteins involved in energy use become more active in resistant tumors. Our recent findings suggest that disrupting these pathways could be a new way to fight these tumors.
In our upcoming study, we will test a compound that acts like glucose but interferes with energy use. We will also test other ways to target the weaknesses of these tumors. Our tests will measure protein and gene activity, energy use, and how combination treatments work.
Funded in partnership with Miami Dolphins Foundation
Cancer immunotherapy has been one of the great advances in the treatment of cancer in the past decade. In B-cell cancers, hijacking T-cells by insbertion of a synthetic receptor (CAR-T cells) enables these cells to recognize and kill lymphoma through a specific marker (CD19). However, despite CAR-T leading to high rates of remission, only about 40% of patients are cured. Some major causes for why CAR-T does not work in patients is too great a burden of tumor cells and the cancer learning to hide the target the CAR-T needs to be effective. Therefore, there is great interest in combining CAR-T with other cancer therapies to improve efficacy. We have a clinical trial combining 2 drugs, mosunetuzumab and polatuzumab, targeting other lymphoma markers (CD20 and CD79b), together with CAR-T in patients with aggressive B-cell lymphomas. Using this approach, we hope to improve outcomes by addressing the main reasons for CAR-T failure. In this grant, we will track a patient’s response to treatment by monitoring a patient’s blood for small tumor fragments, to allow us to determine when extra therapy is needed in addition to CAR-T. We will precisely measure the amount of target markers on lymphoma cells to assess its importance for success of this therapy. Lastly, as CAR-T therapy has a high risk of infection, we will monitor recovery of the immune system to learn how adding extra therapies may affect a patient’s risk.
High-grade gliomas represent the leading cause of brain cancer-related death in both children and adults. A fundamental shift in our approach to glioma therapy is thus in dire need. Though much of cancer research has focused on attacking the malignant tumor cells, our focus here is to target the surrounding tissue that provides growth cues for the cancer to thrive. I recently discovered that one important cue for pediatric gliomas is the activity of neurons within the brain. We found that pediatric gliomas grow at a faster rate in response to elevated nervous system activity. Our work has led us to the discovery that these tumors directly communicate with electrically active neurons by plugging into the neuronal network to receive growth signals. These studies highlight the unexplored potential to target neuron-glioma circuit dynamics for therapy. We propose to take a unique new approach to treating these cancers by interrupting the electrical activity across these cancerous circuits. We aim to reframe our understanding of these tumors by investigating how they integrate electrical inputs and hijack normal mechanisms of brain development. A comprehensive understanding of these dynamic network interactions may lead to new therapeutic interventions aimed at normalizing the tumor microenvironment.
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