Funded by the Dick Vitale Pediatric Cancer Research Fund
Acute Lymphoblastic Leukemia (ALL) is a common cancer in kids. There are two types, B-ALL and T-ALL, depending on the type of white blood cells affected. Most kids get better with current treatments, but sometimes the cancer comes back and we can’t help them anymore. That’s why we need new treatments for T-ALL.
We know that certain drugs used in the hospital affect how leukemia metabolism works. So, we wondered if changing the diet could also help. In our lab, we tried different diets on mice with leukemia. Surprisingly, we found that removing just one component of the food (an amino acid), made a big difference. Leukemic mice eating food without this amino acid lived much longer. Now we want to understand why this dietary approach helps and if we can use it in combination with other treatments. We will study mice with leukemia and samples from real patients to see how this amino acid affects cancer. We also want to find out if combining this diet with current treatments works even better.
If our research is successful, we can try it on real patients. We want to see if reducing this amino acid in the diet can make treatments safer and help more kids survive, especially those whose cancer has come back. This research is important because it could give us new ways to treat leukemia and help more kids get better. It might even help with other types of cancer too.
Funded by the Dick Vitale Pediatric Cancer Research Fund with support from Hockey Fights Cancer in honor of Ben Stelter
Neuroblastoma (NB) is a type of childhood cancer that is difficult to treat after it has spread throughout the body. Using animals that develop aggressive NB, we found different types of tumor cells that may lead to cancer spread. We are proposing to look very closely at these different tumor cells and determine how they may lead to NB spread and drug resistance in patients. We will also test new targeted drugs for their effects on NB spread and through our studies, new ways to treat aggressive childhood cancer may be found.
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.
Funded by the Dick Vitale Pediatric Cancer Research Fund
Brain tumors are the leading cause of cancer-related death in children. While recent advances in neuro-oncology have helped us understand the biology of what is causing brain tumors to develop and grow, many children with brain tumors will still have a dismal prognosis. These tumors can be refractory to upfront treatment, such as radiation or chemotherapy, and there is need for better options. CAR T-cell therapy is a new type of treatment that uses the patient’s own immune cells and modifies them in the lab to recognize and kill cancer cells. CAR T-cell therapies are highly specific to the cancer cells. In our clinical study, we are evaluating the safety and anti-cancer activity of CAR T cells for pediatric patients with brain tumors.
Funded by the Dick Vitale Pediatric Cancer Research Fund with support from the Marc and Peg Hafer Family
Acute myeloid leukemia (AML) remains one of the most difficult leukemias to treat. Pediatric patients with AML have relied on standard toxic chemotherapy and bone marrow transplantation for the past few decades for treatment without any advancement in the development of targeted therapeutics for this disease. The development and clinical investigation of a new class of orally available drugs, called Menin inhibitors, has shown great promise in patients with specific, hard-to-treat subtypes of AML. However, we have recently described acquired resistance to Menin inhibitors through genetic mutation in the Menin gene during treatment. After characterizing and understanding the mutations in Menin, we now aim to try to overcome and possibly prevent resistance with the next generation of Menin inhibitors or with combinations with other drugs that show promise in treating AML. The experiments proposed here will guide the clinical implementation of Menin inhibitors into the standard of care in children with either newly diagnosed or refractory AML. We hope/expect that these approaches will, over time, supplant the need for chemotherapy much as has been the case for targeted therapy in APML, which previously required bone marrow transplantation, but is now cured with two oral therapies that have minimal toxicities.
T cell therapy, like CAR-T, utilizes our body’s own immune defense to fight against cancer. While CAR-T therapy has worked well for some types of blood cancers, it faces challenges in solid tumors like breast cancer. One problem is that CAR-T cells don’t kill cancer cells effectively in the suppressive environment of solid tumors although they can target them. They can also cause harmful side effects by over-releasing cytokines in the body. Another challenge is that making CAR-T cells from a patient’s blood takes a lot of time and money. To overcome these challenges, my lab is developing programmable viral particles that can target tumor like CAR-T cells while bypassing the limitations of CAR-T therapy. In this project, we will engineer CAR-T mimic viruses that can target breast cancer cells and deliver gene circuits to them. These gene circuits can make cancer cells suicide or reprogram them to turn “cold” tumor “hot”. The unique feature of these viral particles lies in their ability to target and rewire tumor environment, their ease of manufacturing, and compatibility with evolving gene circuit technologies. We hope that these innovative anti-tumor viruses will become a versatile and accessible treatment that can synergize with other therapies to enhance cancer treatment.
Funded with support from the Scott Hamilton CARES Foundation
The human body’s immune system is a powerful weapon against cancer, but cancer can also create a complex environment that weakens immune system effectiveness. This environment, called the tumor microenvironment (TME), is made up of different cell types, including tumor cells and immune cells. Scientists have discovered a protein called STING that can change the TME and activate the immune system to fight cancer. However, STING therapy hasn’t worked well in clinical trials because tumors have become resistant to it. To activate STING, researchers use a small molecule called cGAMP. Treatment of cancer with cGAMP can activate STING in various cell types within the TME. When cGAMP is delivered to most immune cells in the TME, it activates STING and triggers an immune response against cancer. However, we found that cGAMP can also be delivered to T cells, which are important cells in killing cancer cells, it actually causes T cells to die. This weakens the immune system’s ability to fight cancer. Therefore, we think that the entry of cGAMP into T cells leads to their death, allowing tumor cells to escape being killed by T cells. Our goal is to identify the specific molecules responsible for cGAMP entry into T cells and develop new strategies to overcome tumor resistance to STING therapy by blocking the entry of cGAMP into T cells.
Funded with support from Carrie Collins in memory of Marty Collins
Immunotherapy helps the immune system recognize and kill cancer and it can cure patients where other treatments fail. Unfortunately, it still does not work for most patients. It is the goal of our research to understand why. Without a clear understanding of how cancer talks with the immune system, and how this conversation changes as cancer progresses, it is difficult to identify the root causes of why immunotherapy fails. Studying cancer evolution in patients is also challenging, as we rarely have the full history of tumor development and there is huge variability between tumors from one patient to the next. Through innovative genetic engineering, we are developing new mouse models of cancer that allow us to carefully study cancer development at all stages of the disease, especially at the moment when tumors acquire the ability to invade into other tissues—the reason cancer is so deadly. Why and how the immune system fails to stop cancer invasion and metastasis is not well understood and is a question of great importance. We will use the models we developed to study this question in creative and powerful new ways. We will also test exciting new immunotherapies, like cancer vaccines, in our models and determine why some tumors respond to treatment and others do not. Through this work, we hope to help match patients with the right immunotherapies and develop better immunotherapies that will be effective for many more patients.
Colorectal cancer is the third leading cause of cancer-related deaths in both men and women. Most people that get colorectal cancer are not genetically predisposed and while the causes are not clear there are three key players in the intestine: 1) immune cells, 2) microbes, and 3) environmental factors such as diet. How these players interact to determine cancer risk needs to be understood. We recently found that mothers can shape intestinal microbes and immune cells for multiple generations by influencing diet in early life (breastmilk). Our big question is, Can mothers protect their offspring from developing colorectal cancer by shaping their immune system? We will use mouse models to address maternal influence on multigenerational colorectal cancer susceptibility. Using a multi-omics approach, we will study the mechanisms of how breastmilk factors shape intestinal microbes and immune cells and protect from colorectal cancer. Our studies will provide the much-needed insight into immune cell-microbe-diet interactions and their role in cancer initiation and progression, and in the future we could harness protective factors in breastmilk to prevent or treat colorectal cancer.
Funded by the V Foundation Chicago Epicurean in honor of Marc Silverman and in memory of Jeff Dickerson
Cells require nutrients to fuel their metabolism to sustain life. Healthy tissues are fed nutrients by blood vessels in a process called perfusion. In contrast, cancers have dysfunctional blood vessels. Compared to normal tissues, blood vessels dysfunction in tumors limits perfusion. This limited perfusion results in abnormal nutrient levels in tumors. We have found that abnormal nutrients in pancreatic tumors blocks the ability of chemotherapeutic drugs to kill pancreatic cancer cells. This is an important finding as pancreatic tumors are resistant to chemotherapeutics, which causes high mortality in this disease. We propose that: (1) identifying the nutrients in pancreatic tumors and (2) how these nutrients lead to chemotherapeutic resistance could lead to new treatments to improve patient chemotherapy outcomes. These are the two critical goals of the proposed project.
To identify the metabolic stresses in tumors that cause chemotherapeutic resistance, we searched for nutrients in tumors that cause chemotherapy resistance. We found that certain amino acids accumulate to high levels in tumors and cause chemotherapy resistance. We will determine if blocking tumor accumulation of these amino acids can improve the chemotherapeutic treatment of pancreatic tumors. Toward the second goal of identifying how amino acid accumulation causes therapy resistance, we will use advanced biochemical and genetic tools to determine how the amino acids accumulating in tumors enable pancreatic cancer cells to survive chemotherapy treatment. Completing aims will provide new insight into how nutrients in pancreatic tumors cause chemotherapy resistance and provide clinically actionable approaches to improve chemotherapy response in patients.
