Funded by the Hirsch Family and the Dick Vitale Gala in memory of Ann Hirsch
Diffuse intrinsic pontine glioma (DIPG) is a fatal brain tumor in children for which the only treatment is radiation and chemotherapy. Sadly, this only results in a temporary relief of the symptoms. Almost all children die of this brain tumor within one year of diagnosis. There is no cure for DIPG. Chimeric antigen receptor (CAR) T cells are a new kind of therapy that has been wildly successful in children with leukemia where there was no hope for a cure. A T cell is a type of immune cell in the body. With CAR T cell therapy, we permanently give the patient’s own T cells a new molecule that shows it how to target then kill the cancer. Dr. Lee was one of the first in the world to treat children with leukemia with CAR T cell therapy and is an expert on its side effects. It has saved many lives so far. Dr. Lee is now making a new CAR in the lab that will recognize and kill DIPG tumors. His approach will be unique because he will add in a way to make the therapy safer and more effective. Once he has made this new CAR, Dr. Lee will use the facilities at the University of Virginia to make DIPG-targeted CAR T cells for patients as part of a planned clinical trial.
Few words inspire more fear than “pancreatic cancer,” and for good reason. Pancreatic cancer is the third leading cause of cancer death in the United States and treatment regimens have changed little, despite these poor outcomes. Researchers have learned a great deal about the genetic mutations that give rise to pancreatic cancer. Yet, we still struggle to apply this information towards more effective treatments. An enormous challenge is that there are different “subtypes” of pancreatic cancer, which makes designing tailored treatments complicated. While studying individual pancreatic cancer subtypes, our lab identified a drug that can selectively kill the most lethal subtype of pancreatic cancer at extremely low doses. This subtype, referred to simply as QM, makes up ~25% of pancreatic tumors and has the worst overall prognosis of all subtypes. Further, because the drug works at such low doses, we may be able to treat patients at doses that do not cause significant toxicity. Here, we propose to define the details of how this drug kills QM pancreatic cancer cells. We will also test whether it can treat pancreatic cancer in mouse models. Finally, we will identify ways that cancer cells could develop resistance to this drug, a frustratingly common outcome. What we learn could help to develop modified versions of the drug or possible combination regimens to overcome resistance. The ultimate goal of our research is to identify new therapies that can be tested in clinical trials.
Vintner Grant funded by the 2018 V Foundation Wine Celebration in memory of Mary Weber Novak
A hallmark of cancer is a defective repair of DNA damage, which supports genetic alterations to drive cancer growth and resistance to drugs. Therefore, effectively targeting DNA repair defects of cancers is perhaps the most attractive strategy to kill cancer cells. Indeed, inhibition of DNA repair by specific small-molecule enzyme inhibitors has proven to be effective in selectively killing breast cancers that already have defective DNA repair function. However, cancer cells frequently develop resistance to these drugs, and therefore there is a critical need to develop safe and effective alternatives to current cancer drugs. A reversible protein modification, called poly(ADP-ribosyl)ation, is essential for DNA repair. ARH3 digests poly(ADP-ribose) to protect cells from poly(ADP-ribose)-mediated cell death. Cells lacking the gene that encodes the ARH3 protein are healthy yet show an increased poly(ADP-ribose)-mediated cell death following DNA damage. This suggests inhibition of ARH3 as an effective strategy to kill cancers with high poly(ADP-ribose) levels. We have found unique structural features in ARH3 that are important for its function, and developed new tools to study the ARH3 function. In this proposal, we seek to develop small molecules that specifically inhibit ARH3 function by focusing on the mechanisms underlying the ARH3 function. Our proposed research will advance our understanding of the role of ARH3 during cellular responses to DNA damage and contribute to the development of new cancer drugs.
“Spirit of Jimmy V” Award funded by the Dick Vitale Gala in honor of Chris Berman
Neuroblastoma is a fast-growing cancer that affects hundreds of infants and children in the U.S. each year. The age of the patient is one of the most important factors for survival. While infants diagnosed before the age of 18 months have a 95% cure rate, older children have only around 50% chance of survival. We aim to improve the treatment options against the more aggressive neuroblastomas in older children.
Recent studies show that a gene called SMARCA4 has a major role in these cancers. We are working to identify all the other genes that depend on SMARCA4 in diseased cells, and then attack the key weak spots. By targeting the whole network instead of a single gene, we will identify new ways to treat neuroblastoma in older children. Our research is a viable first step to improve survival and quality of life for children affected by neuroblastoma.
A new approach to treating cancer is to use each patient’s natural immune system to attack their tumor. This approach takes advantage of the fact that cancer is caused by mutations that occur only in tumor cells. We now know that these mutations allow the immune system to see a tumor as a “foreign” invader, almost like a viral infection. This knowledge has led to the idea that we could design cancer vaccines. Each vaccine would be unique to each patient and train their immune system to attack their unique tumor. The vaccine treatment involves injecting small amounts of harmless pieces of tumor protein into the arm of each patient. Cancer vaccines are promising because they have few side effects compared to other cancer treatments. If cancer vaccines are to be a success, we need to become good at finding the tumor mutations that are best for training each patient’s immune system. So far, early attempts to find good mutations have focused on the simplest and smallest forms of mutations. In some patients, we do not find the right mutations to create a vaccine. In our study we will explore a type of larger and more complex mutation that causes incorrect assembly of proteins in tumor cells. These provide more options for vaccine design. Finding such mutations should lead to better cancer vaccines. Our study should also allow us to design vaccines for more patients and help us to understand what makes a good cancer vaccine.
Vintner Grant funded by the 2018 V Foundation Wine Celebration in honor of Karen Aldoroty
Immunotherapy is a very promising new treatment that uses the body’s own immune system to recognize and fight cancer. This research project focuses on immune cells called macrophages, which are a group of white blood cells in the body. Previous studies have showed that when cancer cells grow in the body, they use signals to protect themselves and escape from macrophages. When treatment was given to block these signals, macrophages were able to recognize and attack cancer cells. In the tumors, in addition to cancer cells, there are many other groups of cells including macrophages. Cancer cells can travel from the primary tumors and grow in organs such as the lung, liver and brain. This caused over 90% of cancer patient deaths. Importantly, these organs also have many macrophages. It is very important to examine if and how macrophages can be used to defend against tumor cells and thus to treat cancer. However, there is much that we do not understand about what exactly occurs during these processes. In this study, we would like to understand how macrophages and cancer cells interact with each other and how macrophages decide if or not they should attack tumor cells. This knowledge will be used to develop new immunotherapies that block cancer cells’ protective traits and allow macrophages to attack and clear them.
“Spirit of Jimmy V” Award funded by the Dick Vitale Gala in honor of Holly Rowe
Fusion-positive rhabdomyosarcoma is driven by a specific fusion gene called PAX3-FOXO1 that acts as a powerful cancer driver. Unfortunately, this fusion gene is not yet able to be targeted directly with drugs. In fact, clinical trials over the past several decades have failed to improve the 5-yr overall survival rate for patients with fusion-positive rhabdomyosarcoma, which remains <50% for all-comers and <10% when metastatic. Prior work from our laboratory revealed that the Hippo pathway, a signaling network that in development ordinarily regulates the growth of organs and tissues, is turned off by PAX3-FOXO1. With Hippo turned off, pro-growth signals are left unchecked and cells become stimulated to proliferative. One of the main signals that gets activated by silencing of Hippo is TAZ, which is a powerful co-activator of cancer-promoting genes. We have seen that TAZ promotes resistance to chemotherapy and regulates the rhabdomyosarcoma cancer stem cell population. Our current studies, which utilize a variety of molecular biology and biochemical approaches in several cell culture and mouse model systems, aim to determine mechanisms by which TAZ controls chemoresistance and stemness. Ultimately, we are seeking to find vulnerabilities within the TAZ/PAX3-FOXO1 axis that can be exploited as novel therapies.
The last 30 years of research have identified more than 500 genes that are mutated (i.e. defective) in human cancer and a lot of attention has been devoted to these mutations. A central mystery that has not yet been solved is why and how the vast majority of cancers show aneuploidy, i.e. the gain or loss of specific chromosomes (chromosome-specific aneuploidy). For example, tumor cells from colon cancer very often (more than 55% of cases) show in their DNA one extra copy of chromosome 13 (normal cells have 2 copies of chromosome 13, cancer cells have 3/4 copies). If scientists are able to understand what are the consequences of chromosome-specific aneuploidy for cancer cells compared to normal cells, then we will be able use this insight to develop new, more effective treatments, i.e. therapies that specifically target cancer cells while sparing normal cells. The goal of this proposal is to unravel this mystery and begin to use this information to design new therapeutic strategies. To accomplish this task, I will be taking a novel approach. First, we will use normal human cells and we will engineer them to contain an extra copy of a specific chromosome. Then we will utilize a series of experiments to comprehensively characterize the biology of the cells containing the chromosome-specific aneuploidy compared to normal cells. We aim to identify molecules that can specifically kill the aneuploid cells compared to the normal cells, in other words we will look for the “Achilles’ heel” of cancer cells.
Historically, antioxidant supplementation has been viewed as an effective prevention strategy against cancer. Despite this, there is growing evidence that antioxidants support cancer growth and lead to worse patient survival. These findings have changed the way we view antioxidants and the treatment of cancer. This is particularly true in a subset of cancers that are driven by an oncogene called KRAS, which can directly engage an antioxidant program to promote survival in cancer cells. The KRAS oncogene is frequently activated by mutations in pancreatic, colon and lung cancers. However, it has proven extremely difficult to find new drugs that directly inhibit activated KRAS. Currently, patients diagnosed with these cancers are given chemotherapy which also have many side effects due to their general toxicity. Thus, the creation of new therapies which specifically target cancer cells, while sparing other normal, healthy cells, has the potential to increase patient survival while improving their quality of life during therapy. Our laboratory has found that the production of antioxidants by NRF2 is essential for the growth and survival of KRAS-mutant cancer cells. To understand how antioxidants are made and used by cancer cells, we use organoid models—cells grown in three- dimensions to study the role of NRF2 in KRAS-mutant cancers. These results will lead to the creation of new therapies which selectively target cancer cells while sparing healthy cells of the body, leading to better patient health and survival.
Metastasis is the spread of cancer to one or more different organs of the body from where it started. The brain is one of the common organs for cancer recurrence. Even with aggressive treatments, brain metastasis is increasingly becoming a significant clinical problem. To find new therapeutic targets to treat brain metastasis, we need to first understand the progression of the disease.
Metastases are generally site specific. The environment of each organ is different. Cancer cells may only be able to colonize one or more specific organs, depending on the primary tumor from which the cells derive. As illustrated in the ‘seed and soil’ theory, tumor cells behave like seeds that can only successfully colonize selective organs that offer the right soil for their survival and growth. Thus, we plan to understand brain metastasis by focusing on the complex conversation between cancer cells (the seed) and brain cells (the soil). Using advanced microscopy techniques, we will directly visualize the metastatic brain tumors in the living animals. Meanwhile, we will detect therapeutic responses when newly designed treatments are applied. From these studies, we will obtain dynamic longitudinal changes in the cancer cells and the surrounding brain cells. This will allow “reconstruction” of the brain metastasis process, as well as therapeutic response. We strongly believe that these studies will yield new ways of fighting brain metastasis.
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