Immunotherapy is a new method of cancer treatment that boosts the immune system to help kill cancer cells. Patients with head and neck cancer that has returned or spread to other parts of the body have few treatment options, and immunotherapy has been a breakthrough to improved survival. However, this therapy works in less than 20% of patients. We believe that this immune system treatment does not work in some patients because their immune system is desensitized to the cancer, and the cancer is able to hide from the immune system. In this study we propose that splicing, which are gene rearrangements, can (1) help identify which patients will benefit from this treatment, and (2) find new ways to make this treatment effective for more patients. First, we will look at splicing as a marker to help predict which patients will respond to immunotherapy. Next, we will use a mouse model of oral cancer to understand how splicing is related to a suppressed immune system to understand why some patients do not respond to treatment. Lastly, we will combine immunotherapy with new drugs that can increase splicing rearrangements to see if this combination will improve response to treatment. Ultimately, we believe that study of these gene rearrangements will lead to new treatments that could help cure more patients with head and neck cancer.
Liver cancer is among the top four causes of cancer death. Historically, liver cancer is driven by HCV. Now, liver cancer is the fastest-growing cause of cancer death in the United States. This is due to the increase of nonalcoholic fatty liver disease (NAFLD), affecting around 25% of the global population. Emerging evidence defines over-nutrition environment and circadian misalignment as risk factors for NAFLD and liver cancer. So far, there is no FDA-approved drug to target the progression of NAFLD to liver cancer. Therapeutic approaches for liver cancer are also limited. Therefore, it is important to understand the mechanisms behind NAFLD-related liver cancer and identify new therapeutic targets.
We reported that a lipid-lowering drug decreased liver fat more when given in the afternoon than when given in the morning. This work is an example of chrono-pharmacology, where giving drugs at specific times of the day can maximize efficacy. My recent work revealed eating time as a key pacemaker for rhythmic metabolic processes in the liver. We can find a potential preventive approach for metabolic disorders and cancer patients by exploring this relationship between the internal clock and eating time. Chrono-nutrition is adjusting diet schedules to maximize results for treatment. The future project will identify how circadian rhythm affects liver cancer cells. These studies aim to find new targets of circadian physiology and reveal insights into liver cancer prevention and treatment.
Funded by the Stuart Scott Memorial Cancer Research Fund
Liver cancer is a leading cause of cancer-related deaths. Its incidence continues to increase, posing a significant threat to public health. A leading risk factor is the chronic exposure to liver stress, which, in turn, enhances the uncontrolled division of cancer cells and tumor growth. Proteins are the functional units within cells. They are made from the instructions stored in DNA and carried by messenger RNA (mRNA) through a process known as translation. Notably, the information stored in DNA is not static and can be modified to alter the outcome of translation to promote cancer growth. Two of these modifications are called ‘RNA oxidation’ and ‘RNA acetylation’, which are induced in liver cells in response to cellular stress, and their levels correlate with tumor growth. Thus, this study will investigate how the interplay between RNA modifications and translation promotes liver cancer. The results obtained in this study will allow for future clinical efforts to fight liver cancer.
Funded by the Dick Vitale Pediatric Cancer Research Fund
Chromatin is the normal form of our genomes and it is formed by DNA and proteins. Chemical changes of these building-blocks, and the factors that control these epigenetic events play essential roles in maintaining the integrity of cells, tissues, and ultimately entire organisms. Recent advances in genomics have uncovered that chromatin and epigenetic regulators are broadly altered in human diseases, particularly in pediatric cancers. This project focuses on understanding how the chromatin regulator Menin helps decipher the chemical language of chromatin, and how it can control or impair gene expression in childhood leukemia. These studies will improve our fundamental knowledge of how protein complexes come together on chromatin and how obstruction of these processes result in the very devastating development of pediatric blood cancers. We use an interdisciplinary approach to provide mechanistic insights into these important questions. This work will shed light into the biology of how Menin regulates chromatin and gene expression, and will pave the way for the development of novel drugs that target these factors in pediatric blood cancers.
Funded by the Dick Vitale Pediatric Cancer Research Fund and the V Foundation Wine Celebration in honor of Jon Batiste and Suleika Jaouad, and Christian and Ella Hoff
Leukemia is a cancer involving a type of blood cell. Some of these cancers can be especially difficult to treat because of their aggressive nature. My lab researches a type of blood cancer that causes death in nearly 4 out of 10 children who are diagnosed with this disease. Based on prior experience, we know that some characteristics of this cancer can lead to worse outcomes in children, but we don’t fully understand all of them. My research aims to discover a more detailed understanding of what causes these cancers to act aggressively, so we can then use this information to find new treatments to cure this type of cancer.
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
Neuroblastoma is a common and deadly childhood tumor. Even with our best treatments, the disease may return. If this happens, our best treatments are not always effective and most patients will pass away. This motivated us to study how neuroblastoma becomes resistant to treatment. Neuroblastoma tumors are made up of different kinds of cancer cells, some of which are sensitive to chemotherapy, and some of which are resistant. Importantly, these different populations can switch between each other, causing sensitive cells to become resistant. How cells do this is not well understood, but may be related to proteins called “transcription factors.” Understanding how resistance occurs may allow us to create new treatments. These treatments could change resistant cells into sensitive cells or stop sensitive cells from becoming resistant. In this proposal, we will use new tools to understand how neuroblastoma cells switch between sensitivity and resistance. We will also use these tools to identify the controllers of these switches. We hope these studies will lead to new ways to treat children with neuroblastoma by targeting resistant cells. We believe this will create new ways to stop this terrible childhood cancer.
Funded by the Scott Hamilton CARES Foundation in partnership with the Dick Vitale Pediatric Cancer Research Fund
Brain tumors are the leading cause of childhood cancer mortality. Two types of these brain tumors, both with mutations in different parts of the histone 3 protein, are both aggressive and deadly. Although these tumors are so awful for the child that has one in their brain, when the tumor is removed with surgery, it is very hard to grow in a dish. For this reason, many scientists take these patient tumor cells and grow them in a mouse. Yet, we and others have seen that although this way of growing the tumors is better than nothing as it allows us to research the tumor cells, the tumor changes a lot in the mouse brain. For this reason, we have generated new models, using transplantation to a cortical organoid. A cortical organoid is a three-dimensional model of the developing human brain made from stem cells. Our work shows this system mimics more aspects of the original tumor, and also provides an opportunity to see how the tumor cells interact with the human brain. We will further optimize this system to study these pediatric brain tumor and we will now begin to ask, which cell types actually cause the tumor to recur after surgery? Which cell types are most invasive, and thus most dangers? Finally, we will also try to identify the cause of these tumors so that we can either prevent them from emerging in children in the first place, or detect them early to prevent tumor progression.
Funded by the Dick Vitale Pediatric Cancer Research Fund
The Schwartz Lab studies two genes, SAMD9 and SAMD9L that are known to cause a bone marrow failure syndrome in children called myelodysplastic syndrome (MDS). There are no reliable pediatric MDS model systems, thus we have created one from a special type of stem cell that contains mutated SAMD9 or SAMD9L. It is important to have these new cell lines, because cells that we can obtain from patients do not grow well or for a long time making studying them very hard. We will perform several tests in our new model system to determine why mutations in SAMD9 and SAMD9L cause blood stem cells to die. Together with our cell lines we have also developed a second set of tools that will allow us to turn on or to turn off SAMD9 or SAMD9L without using interferon—an inflammatory substance in the cell that turns on many other cell processes including SAMD9 and SAMD9L. We have completed initial experiments that suggest that SAMD9 and SAMD9L are important in how cells communicate during inflammation and other immune responses. Our proposed experiments will further determine how disease-causing mutations in SAMD9 and SAMD9L disrupt communication in these important cellular pathways. Understanding how SAMD9/9L mutations effect the blood stem cells will help us determine the right treatment approach for patients with pediatric MDS, because some patients with SAMD9 or SAMD9L mutations may not need treatment at all.
Funded by the Dick Vitale Pediatric Cancer Research Fund and the V Foundation Wine Celebration in honor of Bob McClenahan
Leukemia is a blood cancer that can be fully treated with anti-cancer drugs in most people. However, many people with leukemia do not respond to these drugs and are at risk of dying. It is not known why some leukemias respond to treatment while others do not. We believe that the type of normal blood cell that becomes leukemic impacts the behavior of individual leukemias. We believe that if a normal blood cell possessing the ability to form many other types of blood cells (in other words, it is a blood ‘stem cell’) turns into leukemia, this leukemia will be hard to treat. On the other hand, if the normal blood cell does not possess such properties – it is a more mature blood cell – this leads to treatable leukemia. In this proposal, we will apply our experience in engineering different types of blood cells (stem cells and more mature blood cells) to become leukemic. We will ask how the type of healthy blood cell impacts the behavior of the resulting leukemia. We will use genetics to understand how the properties of normal blood stem cells are transferred to leukemia cells to impact aggressiveness. We expect that successful completion of this study will improve our understanding as to why some forms of leukemia are treatable and why some are not treatable. We hope that these conclusions can lead to better understanding of individual patient leukemias and improved treatments.
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