Designed to identify, retain and further the careers of talented young investigators. Provides funds directly to scientists developing their own independent laboratory research projects. These grants enable talented young scientists to establish their laboratories and gain a competitive edge necessary to earn additional funding from other sources. The V Scholars determine how to best use the funds in their research projects. The grants are $200,000, two-year commitments.
Invasive ovarian cancer is one of the deadliest types of cancer in the world, as less than 30% of these patients remain alive after 5 years. Treatment options are limited for these women, as they usually do not respond well to a new type of therapy that uses the patient’s own immune system to fight cancer. This is despite the fact that ovarian cancer does often have high numbers of T cells – an immune cell that has an ability to kill cancer cells. Therefore, identifying ways to improve the T cell’s ability to kill ovarian cancer cells will likely improve the outcome of these women. To this end, we have discovered a mutation in a molecule found in ovarian cancer cells that is associated with an improved outcome. Importantly, we have found the mutated version of this molecule is linked with increased T cell activity in ovarian cancer. Therefore, our study is designed to understand the connection between this molecule and immune cell activity. Our work will explain a new way that T cells in ovarian cancer can be stimulated to kill cancer cells and will improve our understanding of how immune activity is orchestrated in this disease. We expect that the completion of this work will drive the development of drugs that can target this molecule in cancer cells to improve responsiveness to ‘immune therapies’ and to significantly improve the outcome of women with ovarian cancer.
Pancreatic cancer remains a devastating diagnosis that is incurable in most patients, killing ~50,000 Americans per year. Treatment options including newer immunotherapy approaches are notoriously ineffective. These grim numbers motivate the search for a new strategy called “interception” that might prevent pancreatic cancer altogether. Interception seeks to target the earliest events in the progression of normal pancreas cells into invasive cancer. While this progression spans over a decade, no interception options currently exist.
We have identified a compelling target for interception. This protein is responsible for maintaining the normal identity of pancreas cells, and its activity diminishes as cells progress to cancer. Furthermore, studies comparing thousands of individuals with or without pancreatic cancer have found that this protein impacts risk of developing pancreatic cancer. Lastly, our team has developed potent drugs that can modulate the activity of this protein.
Our goal in this proposal is to pioneer an interception strategy by pharmacologically boosting activity of this protein to prevent progression of normal pancreas cells into cancer. We will characterize the mechanisms and impacts of these new drugs in mouse models of pancreatic cancer as well as in human specimens. Our studies will lay groundwork for clinical trials of interception to prevent pancreatic cancer altogether. Pancreatic cancer interception can also help address issues of psychological trauma associated with diagnosis and unequal access to treatment. Like taking aspirin to prevent heart disease before it happens, we envision these new drugs will be transformative in the fight to end pancreatic cancer.
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.
