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.
Immune cells are always patrolling our intestines, even when we are healthy. This includes B cells, which produce antibodies. Antibodies are floating molecular fire extinguishers which bind to and neutralize infections. In our intestines, huge amounts of antibodies are made every day. These bind to the ‘friendly’ bacteria that we live with to make sure they are well balanced, which keeps us healthy. In inflammatory bowel disease (IBD), the intestine becomes damaged by the immune system and antibodies change which bacteria they bind to. This turns the population of gut-bacteria from friendly to harmful, and can cause IBD to become colorectal cancer.
We do not know which B cells make cancer antibodies, or how antibodies make bacteria harmful. To understand this, we need to know how dangerous B cells become selected to produce the antibodies that turn IBD into cancer. This requires special tools to tell the helpful cells apart from the harmful ones. We built mice with multicolored B cells so we can follow the B cells that become hijacked during IBD and cancer. We may then understand where cancer-causing antibodies are made, and what they bind to. By doing this, we hope to compile a list of common antibodies that are always made before IBD becomes cancer, and look for them as warning signs in IBD patients. This could give doctors more time to treat high-risk patients before tumors form. In the future, we hope our findings help design new cancer drugs to delete harmful B cells.
One challenge of lung cancer treatment is that cancer cells thrive in a tumor ecosystem (or habitat) that protects them. This tumor ecosystem consists of immune cells, blood cells, connective tissue that allow lung tumors to grow and spread to organs (brain, bones, liver, lungs). We recently discovered that PD1, AXL and STAT3 signals in lung cancer serves as “on switches” that drive lung cancer growth, treatment resistance and spread to organs. More importantly, these cancer signals allow cancer cells to communicate with nearby cells for protection. We found that blocking PD1, AXL and JAK signaling can block communication between tumor and non‐cancer cells in tumorecosystem. Our research team would like to perform mouse experiments and clinical trial using drug combinations that turn off these signals and disable the tumor within its habitat, thereby preventing tumor growth and spread. This therapy could help improve survival for our patients with lung cancer.
The rates of rectal cancer are increasing in young adults. Treatment for rectal cancer includes chemotherapy, radiation, and surgery. These therapies can have a negative effect on the quality of life of survivors. Radiation can cause infertility and problems with bowel and bladder function, as well as sexual health. Up to one third of the patients need a permanent colostomy so they do not have normal bowel function. Due to these issues, there has been an interest in finding ways to improve treatment for rectal cancer so that radiation and/or surgery may not be necessary. One way we are trying to improve treatment of cancer, including rectal cancer, is with immunotherapy. Immunotherapy empowers the patient’s own immune system to fight cancer. When this happens, it is very effective. Funding from the V Foundation will support a clinical trial that will treat rectal cancer that is mismatch repair proficient with immunotherapy first. The project team believes that improved immunotherapies like Botensilimab (anti CTLA4) and Basltilimab (PD-1), and earlier treatment before the tumor has spread, will lead to responses. This research has the potential to change the treatment paradigm of all early-stage rectal cancers and omit radiation and surgery in those patients whose cancers disappear with immunotherapy and chemotherapy alone. This will be an important finding for patients’ quality of life. It will also teach us how to make the immune system work against cancers where it has not worked in the past.
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