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.
Funded in partnership with Miami Dolphins Foundation
Pancreatic cancer is a really bad disease that’s hard to treat. Even though treatments like immunotherapy have helped with other cancers, they haven’t worked well for pancreatic cancer. Some people get pancreatic cancer because of a problem gene passed down in their family, like BRCA. We tried treating these people with a mix of immunotherapy drugs, and it worked amazingly well for a few. Their cancer completely went away, and they stayed cancer-free for over 5 years. Now, we’re trying to figure out why it worked for some and not others. We are doing some lab experiments in mice with pancreatic cancer and it seems like something in the cancer cells called STING might be the main reason why this treatment is working. We want to study more tumors from people with pancreatic cancer and the BRCA gene problem to confirm this. Also, we plan to do more tests on mice to see if we can make STING work better in those that don’t respond to treatment at first. If these tests work, it could help create a new treatment for pancreatic cancer in the future.
Uveal (ocular) melanoma (UM) is a rare type of eye cancer. When the cancer spreads to other sites in the body, outcomes are often poor. Unlike skin melanoma, UM does not respond well to new types of therapy focused on the immune system. Better treatments are urgently needed. Our lab has recently shown that UM tumors frequently lose a sex chromosome (Y in tumors from men, X in tumors from women). Loss of the male Y chromosome (LOY) in men and loss of one X chromosome (LOX) in women occurs in about half of tumors, thereby affecting many patients. We found that LOY is linked to worse survival, and that LOY and LOX can give clues whether a patient’s tumor will spread to other sites in the body. I now propose to study the exact role of LOY in UM with a combined approach. Using genome analysis, gene knock-outs and drug screens in uveal melanoma models, our team hopes to find the weaknesses of UM tumors with LOY. These weaknesses could suggest new treatments for patients. LOY is not limited to UM but also occurs frequently in other tumor types. Therefore, the proposed work has far-reaching implications for finding better treatments for many people living with cancer.
The immune system is your body’s resident doctor. Immune cells constantly examine the organs and tissues in your body. Most of the time, immune cells eliminate damaged or infected cells before they can make you sick. However, this process goes wrong in cancer. We now know that tumors use multiple strategies to hide from immune cells so that they can grow and spread throughout the body.
A new kind of medicine, called immunotherapy, teaches the immune system to recognize and destroy cancer. Some patients treated with immunotherapy cleared their tumors and remained in remission for decades – the closest we’ve come to a cancer cure. However, most patients with colorectal cancer, the second deadliest cancer in the US, do not benefit from existing immunotherapies. It is thought that these patients’ cancers have developed different or additional strategies to hide from immune cells – but how?
One way that immune cells examine cancer cells is by detecting the sugars, or glycans, they display on their surfaces. It was recently discovered that colorectal tumors decorate their surfaces with sugars that trick the immune system into thinking the tumor cells are healthy cells. Thus, glycans are emerging as a main strategy used by colorectal cancers to evade the immune system. This project will develop medicines that target these glycans as a new kind of immunotherapy. Our hope is that medicines targeting sugars can help improve outcomes for all patients with colorectal cancer.
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