Funded by Lloyd Family Clinical Scholar Fund
Ovarian cancer (OC) is the most lethal gynecologic cancer in the US. Unfortunately, the majority suffer relapse. Patients with recurrent platinum-resistant OC respond poorly to chemotherapy.
Immunotherapy with immune checkpoint inhibition (ICI) has emerged as a promising therapy in several cancers. Unfortunately, only small fraction (10-15%) of patients with OC do benefit from immunotherapy. Therefore, effective strategies are warranted to improve the overall benefit of immunotherapy in OC. Targeting immunosuppressive factors within the tumor immune microenvironment (TME) represents an attractive approach. Our focus in this proposal is on tumor-associated macrophages in OC.
Macrophages with a specific ‘suppressor’ phenotype (M2 subtype) within TME play a significant role in promoting an immunosuppressive environment and in mediating therapy resistance. These cells are the most prominent cells in OC. However, another phonotype (M1 subtype) provides a favorable pro-inflammatory TME and enhances the immune response. Targeting macrophages and switching their phenotype from M2 to M1 is potentially promising approach that has not been investigated thoroughly before. In this study, we propose to target them with two strategies: Targeted inhibition of the transforming growth factor-beta (TGF-beta) receptor and CD47 inhibition.
Funded by the Stuart Scott Memorial Cancer Research Fund
Adult midline gliomas are aggressive, unresectable tumors for which no curative treatments exist. These tumors are caused by faulty ‘epigenetics’ i.e. problems in the way cells switch certain genes ‘on’ or ‘off’. Our research is studying a protein complex called PRC1, which we have found these tumors use to keep certain genes switched off to promote growth. We aim to understand how PRC1 functions so that we can devise novel ways to target this pathway and develop new treatments for this disease.
Lung cancer kills the most cancer patients in the world. Most of these patients are diagnosed late in their disease, and there is no cure. Having a chest CAT scan (CT scan) every year helps detect lung cancer early and reduces the chance of dying. When lung cancer is detected early, the patient has a higher chance to survive. Patients who are diagnosed with small lumps in their lungs, called lung nodules, have a higher chance of getting lung cancer. Having lung nodules can also require unnecessary, uncomfortable, and sometimes painful medical procedures that are not helpful for the patient. The purpose of our research is to help detect lung cancer earlier for patients with lung nodules, which could give them a better chance to beat cancer and survive. To do this, we propose to combine new medical test tests, from a blood draw and computer measurements from CAT scans. We will use simple blood draws to measure DNA materials in the blood that can help detect if lung cancer is present. We will also use computers to analyze hundreds of measurements from lung nodules in CAT scans that can tell us if the nodule is cancer. We will then combine the blood draw and computer measures from CAT scans using advanced math to detect lung cancer early more accurately without hurting the patient. Our goal is to improve early lung cancer detection so that it can be cured and help save patient lives.
Funded by the Dick Vitale Pediatric Cancer Research Fund
KMT2A acute lymphoblastic leukemia (KMT2A ALL) is the most common ALL subtype in infants and common in older children with ALL. It is a deadly disease that does not respond well to chemotherapy treatments and often returns. Our goal is to identify new medicines that can improve the health of patients with this disease. Our studies show that KMT2A ALL need the signaling molecule DYRK1A to multiply and grow, a process called cell proliferation. DYRK1A regulates cell proliferation by transmitting information to other signaling molecules. Using a specific DYRK1A inhibitor slowed down cell proliferation but did not kill KMT2A ALL cells. Our study showed that one molecule is important for protecting KMT2A ALL cells against DYRK1A inhibition. This molecule is called BCL2. We are now testing using a two-medicine treatment approach if inhibition of DYRK1A and BCL2 can kill KMT2A ALL cells. If this new treatment approach proves to be better than current chemotherapy treatments, we aim to test this new strategy in patients.
Funded by the Dick Vitale Pediatric Cancer Research Fund
Pediatric cancer patients have greatly benefited from advancements in CAR-T cell therapy, a cancer treatment in which a patient’s own T cells – a type of immune cell – are reprogrammed to recognize and kill cancer. CAR-T cell therapy has demonstrated remarkable clinical success and can even cure some patients; however, only 50% of those treated remain cured after 12 months. A major roadblock preventing this therapy from curing more patients is poor CAR-T cell survival. Patients with long-lived CAR-T cells are more likely to be cured than those with short-lived CAR-T cells. Therefore, there is an urgent need to develop strategies that help CAR-T cells stay in the fight against cancer.
My research project will test a new approach that helps CAR-T cells survive longer by tapping into the natural biology that helps T cells persist in the body. By forcing CAR-T cells to act more like naturally occurring long-lived T cells, we can boost their ability to survive and kill cancer. We will also determine the molecular “secret sauce” that allows some patients’ CAR-T cells to persist for longer compared to others. Collectively, this project will help advance more efficacious therapies for blood cancers and potentially other types of cancer in both children and adults, and reveal valuable information about CAR-T cell persistence that can be leveraged for future discoveries.
Funded in partnership with WWE in honor of Connor’s Cure
Brain tumors are the largest cause of cancer-related death in children. A subgroup of brain tumors known as DMG are the deadliest type, with most children dying within two years of their diagnosis. The location of these tumors makes surgery difficult and there is a need for effective therapies. One hallmark of DMGs is de-regulated (meaning too much or too little) epigenetics. DNA is a language in each of us that translates a set of instructions, determining features like our eye and hair color. Epigenetics provides the structure that allows cells to decode the DNA instructions for proper function. Patients with DMG have changes that result in faulty instructions that make cancer cells grow faster or migrate to other parts of the brain and body. A second emerging hallmark of DMGs is distorted metabolism, which is the chemical reactions in the body’s cells that change food into energy. We have made the discovery that brain tumor epigenetics is highly dependent and linked on certain nutrients. These nutrient sources help brain tumor cells to hijack epigenetic reactions to promote growth. By reducing the fuel that the cancer cells rely on, we aim to kill brain tumor cells while leaving normal cells unharmed. Why is this important? Pediatric brain tumor research has not generated sufficient advances and this proposal aims to help address that.
Parker Bridge Fellows Program; Funded in partnership between Parker Institute for Cancer Immunotherapy and the V Foundation
Using the immune system to fight cancer is an exciting area of research that has led to cures for some cancers that could never be cured before. These “immune therapies” teach and enable cells in the immune system to recognize and fight cancers. Unfortunately, making effective immune therapies is difficult for deadly cancers of the brain. One challenge is that immune cells are not able to get into the brain as easily as other parts of the body. Another challenge is that the cells in the tumor can suppress the immune system, so that even when immune cells enter the brain, they cannot kill the tumor. We are interested in studying how cells interact inside of tumors to better understand why some immune cells are effective at killing tumors and others are not. My research uses a new kind of microscope imaging to see tumor cells and immune cells with more detail than ever possible before. This allows our lab to look at the structure of brain tumors to better understand how immune cells enter the brain and interact with other cells in the tumor. By understanding better how brain tumors and immune system influence each other, we hope to make more effective immune therapies to treat this deadly type of cancer.
Acute myeloid leukemia is the deadliest blood cancer. The mainstay chemotherapeutic treatments have met with limited success, and most patients will die from their disease. Thus, New treatments are desperately needed. To address this need, we have identified a cellular pathway leukemia cells rely on to live. In this project, we have developed an inhibitor that blocks this pathway and found that it kills leukemia grown in mice. We would like to understand why some leukemia cells rely on this pathway to survive and what determines the response to the inhibitor. If successful, our work will provide preclinical evidence for a new pathway as a target for acute myeloid leukemia and offer needed knowledge and chemical tools to guide future clinical studies. We are hopeful that our findings could lead to improvements in the lives of AML patients.
Acute myeloid leukemia (AML) is an aggressive blood cancer that can recur after standard therapy. Although chemotherapy kills fast-growing AML cells, it often fails to destroy all cancer cells. As a result, the patient may appear to respond to therapy, but eventually the cancer returns. We found that the surviving cancer cells can overcome therapy by entering a senescence-like dormancy, allowing them to endure chemotherapy and resume cancerous activity after therapy has ended. The cancer cells become more aggressive than before treatment and showed changes in their epigenetic marks including DNA methylation. In this project, we will examine the mechanisms controlling the DNA methylation changes and their role in AML dormancy. Overall, this project will advance our understanding on the relevance of DNA methylation in cancer therapy and will define new therapeutic targets. Our long-term goal is to apply this information to develop new therapies to improve the survival of AML patients.
Funded in partnership with the Cancer Research Institute through the V Foundation’s Virginia Vine event and Wine Celebration Fund-A-Need
Our immune systems are internal barometers for the primary response to foreign invaders like viruses and bacteria within our body. Despite cancer arising from irregular growth of our own cells, the immune system can effectively kill cancer cells just as it identifies and kills infected cells. However, cancer can also effectively hide from the immune response (known as immune evasion), specifically because it grows from our normal cells becoming mutated or unchecked. Thus, preventing immune evasion and augmenting the immune response are now the focus of new and promising treatments. The immune cells found in cancer can be classified by function, helpers, killers, and suppressors. Helpers educate the killers. Killers directly attack and eliminate the tumor cells. Suppressors hinder the immune response and promote cancer growth. Most immune-based therapies target the killers, however, there are many other components of the microenvironment in which cancer grows. In addition to the helpers and suppressors, the “soil” in which these cells thrive is important. We aim to understand how the “soil” (known as mesenchymal stem cells, MSCs) influences two key immune components in ovarian cancer patients, helper educational centers known as tertiary lymphoid structures (TLS) and suppressive T cells known as T regulatory cells (Tregs). Understanding this interplay is paramount to generating new and effective therapies for ovarian cancer patients, which is especially important in ovarian cancer because patients have not garnered the same therapeutic benefit with immune-based therapies as other solid tumors. In fact, only ~10% of ovarian cancer patients receive a survival benefit with immune-based therapies. Why is this? What is unique about ovarian cancer than allows it to effectively hide from the immune system?
In ovarian cancer, the balance of the immune response is often tipped to enhance the suppressors, thus killers cannot effectively target and kill the tumor cells. We aim to determine how to increase the “soil” (MSCs) that promotes helper TLS and prevents suppressive Tregs utilizing novel therapies. “Soil” cells which start in the bone marrow (BM-MSCs) can initiate the building of helper TLS. Thus, these BM-MSCs work with the immune system to increase anti-cancer immunity. “Soil” cells that develop within the ovarian cancer environment (CA-MSCs) can help enhance ovarian cancer growth by amplifying the suppressive function of Tregs. Thus, these local CA-MSCs work against the immune system to decrease anti-cancer immunity.
Altering the immune balance by targeting both the immune cells and the MSCs offers powerful new combinatorial treatment approaches. Our goal is to understand the specific factors within the ovarian cancer environment which impact this immune balance and to develop treatments to shift this balance to kill ovarian cancer. Specifically, we will study the steps necessary for BM-MSCs to support TLS formation and immune activation. We will also identify how local CA-MSCs recruit Tregs to decrease the immune response. We will specifically test if blocking the interaction between CA-MSCs and Tregs will shift the balance of immunity towards killing cancer.
This work can be quickly moved into clinical trials as the blocking drug we are testing (neuropilin-1; NRP1) is already in early clinical development and our team includes an ovarian cancer clinician and translational immunologist with experience writing, conducting and analyzing clinical trials. The vision of the Clinic and Laboratory Integration Program (CLIP) is to improve the effectiveness of cancer immunotherapies. This grant will meet this vision by developing a therapy that targets MSCs and the immune system for a synergistic effect on improved patient outcomes.
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