Patrick Grohar, MD, PhD

Funded by the Constellation Brands Gold Network Distributors in honor of the Dick Vitale Pediatric Cancer Research Fund

Ewing sarcoma is a cancer that is most often diagnosed in teenage children and young adults. There is a need for new therapies for this disease. The goal of our work is to develop new therapies for Ewing sarcoma focused on a drug target called EWS-FLI1. Multiple studies have shown that EWS-FLI1 is a promising drug target for this disease. In a clinical trial called SARC037, we are currently testing a combination therapy that we have shown targets EWS-FLI1. The goal of the current study is to try to understand why some patients in this trial respond to the therapy and others do not. To accomplish this, we will study ways that EWS-FLI1 resists targeting. We will identify molecular differences in tissue collected from patients who had an excellent response to the therapy compared to those who did not respond. In addition, we will test these differences in the laboratory to see how they impact sensitivity to the therapy used in SARC037. The results will guide future clinical studies that seek to target EWS-FLI1. In addition, they will provide insight into how EWS-FLI1 contributes to drug resistance to more traditional chemotherapy.

Maayan Levy, PhD & Bryson Katona, MD PhD

Colorectal cancer (CRC) is a common and deadly cancer that often arises from abnormal pre-cancerous growth of polyps in the colon. Colonic polyps can be detected and removed during colonoscopy, therefore reducing the risk of cancer development. While most CRC cases occur randomly, about 25% of CRC cases have a familial component, including hereditary syndromes like Lynch Syndrome and Familial Adenomatous Polyposis (FAP).

Individuals with FAP have a very high susceptibility to developing CRC, requiring frequent diagnostic testing. However, for FAP patients, the number of colon polyps is often too high to be removed through colonoscopy. In these situations, patients may require surgery to remove their colon, which is costly, has risks, and changes bowel movement habits. Therefore, finding new ways to slow down the development of polyps and CRC would greatly benefit FAP patients.

Using mouse models of FAP and an intervention study in FAP patients, our study aims to develop a new approach to prevent CRC in FAP, called chemoprevention, by exploring the potential of a new substance to reduce the development and/or progression of colon adenomas. We have observed that beta-hydroxybutyrate (BHB), which is a natural substance that our bodies produce while in a starving state or when on a ketogenic diet, can slow down colon tumor growth. As there is currently no standard chemoprevention treatment for FAP, our study aims to address this critical need for effective approaches to reduce CRC risk and improve the lives of those with genetic conditions that lead to colon cancer.

Juliana Hofstatter Azambuja, PhD

Funded in partnership with WWE in honor of Connor’s Cure

Diffuse midline glioma (DMG) is a devastating and aggressive type of brain tumor that primarily affects children and young adults. Despite advancements in medical research, DMG remains a medical challenge with limited treatment options and a poor outcomes. Considering these difficulties, there is an urgent unmet need to develop new and innovative therapies for DMG. One promising avenue for discovery is the exploration of targeted agents that disrupt key signaling pathways involved in tumor progression without affecting the healthy normal cells in the brain. Our previous work has identified a potential new therapeutic target that could be leveraged in this way to specifically combat this tumor. New drugs that selectively inhibit this aberrant signaling pathway show great potential for slowing down the growth of DMG cells, thus creating a new opportunity for intervention. In these proposed studies, we will explore precisely how this intracellular signaling pathway controls cancer progression. Further, we will test in the lab whether treatment with new drugs designed to inhibit this pathway can halt DMG tumor growth. We hope that our studies inform the use of new targeted drugs to treat this devastating childhood cancer and thereby drive advancement of patient care and redefine the treatment of DMG.

Haider Mahdi, MD

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.

Richard Phillips, MD, PhD

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.

Despina Kontos, PhD

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.

Christian Hurtz, PhD

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.

Evan Weber, PhD

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.

Sameer Agnihotri, PhD

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.

Derek Oldridge, MD, PhD

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.

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