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.
Funded by the Tyler Trent Fund and the Dick Vitale Pediatric Cancer Research Fund
A critical failure in the field of pediatric thyroid cancer care is the use of adult treatments for a childhood disease that has distinct genetics and tumor behavior. With thyroid cancer incidence rapidly increasing, we need to develop personalized treatments for this population to ensure their long and productive lives. There is currently no way to predict which children will go on to develop recurrent or aggressive disease at the time of biopsy and thyroid surgery. While thyroid cancer is generally curable, adolescents and young adults present with more frequent local and metastatic disease when compared to older adults. Adult treatment protocols lead to high cure rates, but adolescents and young adults have many years of potential recurrence, radioactivity-induced side effects, and secondary malignancies ahead. Precision medicine is becoming the standard of care for many diseases except pediatric thyroid cancer.
To develop more individualized pediatric thyroid cancer care, the scientific community must first strive to better understand the mutations and abnormal cellular signaling responsible for thyroid cancer behavior. Our research program utilizes a large cohort of adolescent and young adult human thyroid tumors in order to study the signaling pathways responsible for the unique growth and spread of each tumor. The funds from the Pediatric Cancer V Scholar Award will lead to an improved understanding of thyroid cancer development in this population and innovative therapies for children with this disease. These treatment strategies can then be applied to a wide range of pediatric cancers with reliance on similar signaling pathways.
Lung cancer is the leading cause of cancer-related death worldwide, killing more than breast, prostate, colon, kidney, and liver cancer combined. Lung adenocarcinoma (LUAD), the most common type of lung cancer, alone kills ~60,000 Americans every year. Therefore, preventing lung cancer would have a large impact on society. Preventing lung cancer altogether would also address the problem of worse outcomes for patients who, for social and economic reasons, have unequal access to cutting-edge cancer treatment. Even patients who are cured of cancer experience psychological trauma, so prevention would also mean that no one would have to go through such a traumatic experience. Our initial results show that early lung cancers are less complex and therefore should be easier to eliminate compared to advanced disease that has spread from the lung to other parts of the body. We propose to study the earliest steps, when a normal lung cell becomes a cancer cell. To do this, we have developed a way to study lung cancer cells in the lab that closely resembles how tumors grow in humans. In addition to studying features of early lung tumor cells, we will also study the surroundings of these cells, a method that has not been used before to study lung cancer. We aim to discover molecular processes that are essential for the formation of lung cancer. Drugs could then be developed to block these processes and stop lung cancer at its earliest stages – preventing the disease altogether.
Funded by the Stuart Scott Memorial Cancer Research Fund
Our immune system operates on a balance of cells that can destroy infected or cancerous tissue and cells that prevent attacking healthy tissue. This balance is affected during cancer where cells that attack the tumor become inactivated. This allows further growth, cancer spread (metastasis) and eventual death of the patient. To address this problem researchers have developed drugs known as immune checkpoint inhibitors. These drugs activate T cells, a type of immune cell, to attack the tumor. Cancer patients treated with these drugs have seen major increases in survival. However, due to these drugs tipping the balance to a more active immune system, it can cause harmful side effects. These side effects cause interruptions in treatment plans which can result in disease progression. Currently, we do not have tests in the clinic that are able to predict these side effects. Therefore, there is an urgent need to understand how these side effects develop. Cancer cells consume abnormal levels of nutrients and release factors that can be sensed by blood circulating cells. We believe that these changes can be sensed by mitochondria. The mitochondria are organelles in cells that regulates energy metabolism. With new technological advancements, we can measure how this organelle changes in function in patients’ blood cells. We propose to test how patient blood cells energy changes. We predict that patients that develop side effects will have a lower cellular energy levels. Our study will provide a marker to predict side effects before they develop. We will also study genes that regulate cell energy metabolism to identify drug targets aimed at reducing the onset of side effects. Therefore, our studies will provide a personalized approach to cancer treatment to improve outcomes while preserving their quality of life.
The Schug laboratory is interested in understanding the way a cancer feeds itself in order to support its growth. The amounts and types of foods that cancers consume can be very different from the ones that our bodies normally use. For this reason, we believe that these differences can be used as new targeted treatment options for cancer patients. We have identified a specific food that is uniquely used by cancers to fuel their growth. Our goal is to create drugs that can block cancer’s ability to feed on this food. In addition, we are exploring the idea of combining this drug with other available treatments to improve patient survival. This research is important because it looks to block behaviors that are unique to cancer and therefore spares the body from harmful side effects. Furthermore, our results suggest that this food source is used by nearly all types of cancer. Because of this, we believe that our research is likely to make a major impact on the lives of many different cancer patients.
Liposarcoma is a cancer that affects approximately 1000 new people per year in the United States and primarily targets adults over the age of 50. Although some cases are successfully cured with surgery if caught early, patients traditionally had few options if the cancer came back or if surgery did not eradicate it, because standard chemotherapy and radiation therapy were not effective. A new class of drugs called CDK4/6 inhibitors has recently begun to change the prospects of these patients. These drugs stop cancer cells from dividing without killing them. In some patients, the same drugs cause the cells to enter what is called senescence: the cells never resume dividing, even when the drug is removed. Senescence normally occurs in cells whose DNA has been damaged, so this exciting new form of senescence called SAGA (senescence after growth arrest), that is triggered by a CDK4/6 inhibitor, is not as well understood. I am working with a collaborator who has begun to study SAGA in liposarcoma tumor cells. I am an expert in mapping how DNA is folded inside the cell nucleus to regulate which genes are expressed (turned on). I propose to use my mapping tools to study how the structure of the genome in tumor cells helps cells to decide whether to enter or stay in SAGA, what genes to turn on, and how we might control these genes using other drugs that can be combined with CDK4/6 inhibitors.
Liquor, tobacco and human papilloma virus (HPV) infection are major causes of head and neck cancer (HNC). Adult males often contract HPV infection via oral sex. People carrying HPV are at higher risk of developing HNC. Current HPV vaccines do not work in people already infected or in cancer patients. In the U.S., one in four persons are HPV positive. Thus, HNC will remain an important health problem for decades because of the high number of currently infected people. The major goal of our research is to design a cancer vaccine that works after disease onset.
Vaccination works by prodding the immune system to make protective antibodies. Our previous research suggests that antibodies against tumors are present for a short time as cancer grows. Now, we aim to learn how antibodies against tumors are made. We will use this knowledge to develop safe vaccine therapies to cure existing disease. Our approach is different because current immune therapies target cellular immunity, that is T cells, whereas we aim to exploit humoral immunity, that is B cells and antibodies.
This work will provide key data to push a patient’s immune system to make more anti-cancer antibodies and cure their disease. These new therapies will avoid marring head and neck surgeries and thus will improve how patients function. Importantly, our therapeutic approach can be extended to any type of cancer.
Medulloblastoma (MB) is a common form of brain cancer and the leading cause of cancer-related death and injury in children. One subtype of MB (MYC-amplified MB) occurs in the cerebellum, the part of the brain that controls movement. However, MB often spreads to other parts of the brain and spinal cord. In roughly one-third of patients, MB has already spread when they are diagnosed. In patients that develop MB more than once, most of them have tumors beyond the brain. The current treatment is radiation of the entire brain and spinal cord, followed by high-dose chemotherapy. This is very harmful to a child’s developing brain and not effective for the spread tumors. New and improved therapies are greatly needed.
Understanding how MB spreads will help researchers develop new treatments and prevention plans. LDHA is an enzyme that plays an important role in tumor development and spread. In healthy tissue, LDHA levels are low. In tumor samples, LDHA levels are extremely high. Blocking LDHA may slow cancer without damaging healthy tissue. Our goal is to discover in the laboratory if targeting LDHA can prevent and treat MB that has spread. Then we will develop clinical trials so that children suffering from this horrible disease can have better results.
Patients with leukemia require new and better medicines. While current drug treatments can often clear most leukemia cells from the body, too often the disease will become resistant. We believe that it is important to find new drugs that target the parts of cancer cells that control how and when specific cancer genes are turned on or off. These systems work at regions of our genome called ‘enhancers’. Enhancers represent the most important circuits of our genome by coordinating what genes are on or off. In cancers like leukemia these circuits are broken. This leads to an altered state of unrestrained growth, survival under stress, and resistance to drugs. In leukemia cells there are many mutations in genes that change how enhancers work, but few drugs to target them. We need a complete toolbox of enhancer-targeting drugs and we are making significant progress – but more work is needed to understand how these drugs work in order to identify the patients most likely to benefit. Our goals with this project are to use new genomics tools to study the effects of a new class of enhancer-targeting drugs that directly block critical signaling factors. These drugs have not yet been studied in leukemia, and we expect that our efforts will lead to future use of this promising new type of medicine.
Inflammation is major risk factor for cancer and is directly linked to at least 20% of all cancers. Our epithelial tissues, such as the gut, lungs and skin, routinely experience injuries and infections that cause inflammation. A vast majority of inflammatory reactions resolve to restore tissue health. Many studies have examined the role of chronic (non-resolving) inflammation in cancer formation and progression. However, how routine acute or resolving inflammation influences cancer formation has not been closely studied.
We have previously shown that acute inflammation fundamentally changes tissue immune environments and epithelial stem cells. This process, called “inflammatory training”, is known to improve responses to pathogens, vaccine efficacy and, we find, enhance tissue regeneration. Using models of squamous cell carcinoma, a deadly cancer that can develop on many epithelial surfaces, we examine how inflammatory training impacts the initiation of tumors. We will study both the tumor forming cells and their microenvironment to determine exactly which factors are changed by acute inflammation that make tissues hospitable to cancer cells. In doing so, we seek to unearth fundamental knowledge of how tumors form and use this information to develop strategies for early intervention to stop this devastating disease in its tracks.
Funded by the Constellation Gold Network Distributors
Over the past several years, immunotherapy has emerged as a highly effective treatment for cancer. In contrast to chemotherapy, which kills cancer cells with toxic chemicals, immunotherapy teaches a patient’s immune system to attack tumors. As current immunotherapy treatments are only successful in~ 30% of cases, scientists are actively searching for ways to create new classes of immunotherapy drugs. One promising treatment works by deactivating proteins that serve as “off-switches” for the immune system. However, we do not understand how several of these switches carry out their functions on the molecular level.
My research group is using two different methods to guide the development of next-generation immunotherapies. Our first strategy is to use a high-resolution imaging technique called x-ray crystallography to “see” how different types of off-switch proteins send signals. By visualizing these molecules on the atomic scale, our goal is to obtain molecular blueprints that can teach us how to design more effective drugs. For our second strategy, we will use these blueprints to create decoy proteins that can block incoming signals from reaching immune receptors. These decoys will then be used to prevent the natural off-switch proteins from shutting down the immune response. Initially, the decoys will be used to re-activate immune cells in a laboratory setting. However, if these tests are successful, our long-term goal is to proceed to clinical trials in melanoma patients.
