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.
Vintner Grant funded by the 2018 V Foundation Wine Celebration in honor of Gina Gallo
One of the deadliest cancers is called Triple Negative Breast Cancer (TNBC). Women with TNBC are more likely to die of breast cancer than women with other types of breast cancer. This type of cancer is more common in African American women.
Treatments for TNBC exist, but we do not know if they are equally effective for all women with TNBC. One reason the outcome might be poorer for African American women is because the standard treatments might be less effective for them. Treatments for TNBC work better when a woman has a certain mutation in gene called BRCA1 and related genes known as RAD51 genes. Unfortunately, this treatment may not work if the gene has been turned off by a mechanism called methylation. This process of methylation is much more common in African American women. In this proposal, we want to find out how frequent methylation of BRCA1 and RAD51 genes occurs in Caribbean populations and then compare the response to TNBC treatment for African American, Caribbean American and European American populations. We hope to find how frequently BRCA1 gene is turned off in breast cancer patients of Caribbean origins and then use this knowledge to assist in the choice of targeted therapy for these patient populations.
Primary liver cancer is a leading cause of cancer death worldwide. Liver cancers are resistant to many cancer drugs. Our immune system has enormous power to find and destroy infectious microorganisms in our bodies, and scientists reasoned that immune cells such as T cells could also find and destroy cancer cells. Using a mouse model of liver cancer, we found that T cells could recognize cancer cells in the liver, however the T cells failed to kill the cancer cells. We discovered that interactions between liver cancer cells and T cells quickly restructured T cells’ DNA. DNA is the program that controls how cells respond and function. The DNA restructuring in T cells took away the T cells’ ability to kill cancer cells. Our goal is to understand how the interaction between liver cancer cells and T cells makes T cells dysfunctional. We are working to develop a three-dimensional liver cancer model in cell culture dishes. We can add T cells to precisely study the earliest changes in T cells after they encounter a liver cancer cell. This will give us clues about why the T cells are shut down their anti-tumor function. We will then test DNA targeting strategies to see if they prevent T cells from becoming dysfunctional. Ultimately, these genetic targeting strategies can be used to activate T cell responses against cancer cells in patients with liver cancer.
Of the cancers that affect both men and women, colon cancer is the second leading cause of cancer deaths and the third most commonly diagnosed cancer in the United States. Interestingly, evidence from the clinic links disruption of normal 24-hour rhythms with many diseases including a higher risk of cancer. Our internal clock controls sleep/wake cycles, feeding and metabolism and disruption of the clock has been reported in several cancer types, including colon cancer. Yet, the precise process of clock disruption in colon cancer remains undefined. We are interested in cells that have the ability to initiate tumors because these cells have been found to be treatment resistant. We propose to determine how loss of the clock can promote colon cancer by changing the cues that direct these cells that initiate cancer. To accomplish this, we have generated a mouse model to understand the effects of clock disruption on cell growth in the intestine. We propose that disruption of both the clock and loss of cues that control normal cells in the intestine can result in colon cancer. The goal of these studies is to provide new directions towards clock-dependent treatments that can target colon cancer.
Vintner Grant funded by the 2018 V Foundation Wine Celebration in honor of Lauren Ackerman
Cancer is considered a disease of the genome because the acquisition of genomic alterations can spur disease progression by disrupting natural checks and balances on cell growth and behavior. These alterations are often a result from exposure to environmental factors, such as UV light or tobacco carcinogens. They also arise as a byproduct of normal physiological processes. One of the most common alterations detected in cancer genomes are mutations that have been linked with our endogenous APOBEC enzymes. The APOBECs normally protect against viral infection by inducing mutations in viral genomes. It is not clear why this potent mutagenic activity turns against our own genomes in the context of cancer. We seek to understand how the anti-viral APOBECs become activated to attack our own genomes and to determine how this activation leads to mutation and cancer growth. We will draw on conceptual parallels between viral infection and cancer-intrinsic processes to gain insights into the mechanisms that drive APOBEC activity in the cancer setting. Our work will set the stage for the development of therapeutic interventions to blunt or leverage this mysterious mutational process.
Multiple Myeloma is a cancer of the bone marrow that cannot be cured. Patients typically receive many different therapies that work initially but some myeloma cells always remain, eventually leading to relapse. This is due to enormous genetic diversity of myeloma in each patient that also changes with every treatment, ultimately leading to outgrowth of drug-resistant myeloma cells. It is therefore crucial to understand why myeloma cells persist despite drug treatment and define the genomics and molecular mechanisms of drug resistance. To do so would require frequent access to myeloma cells from bone marrow biopsies. However, the current standard of care, a bone marrow biopsy from a single site at time of diagnosis, is not sufficient to capture the diversity and constant evolution of myeloma. We are proposing to use novel “liquid biopsy” approaches we developed to replace bone marrow biopsy using circulating multiple myeloma cells and cell-free myeloma DNA that we obtain from a simple blood draw. Our hypothesis is that liquid biopsy will allow us to obtain more comprehensive genomic characterization of myeloma than bone marrow biopsy, with less risk and discomfort for patients. With the use of novel technology we can also obtain comprehensive genomic and molecular information from very few cells when patients are in remission and no myeloma is detectable with conventional methods. We can use this technology to test if genomic events that cause drug resistance predict relapse. These approaches may replace bone marrow biopsy and identify molecular mechanisms that drive resistance to therapy.
Prostate cancer is currently the second leading cause of cancer death in men in USA. Although surgical intervention and other first-line therapies for prostate cancer have improved over the past decades, there is still no effective cure for patients suffering from advanced/recurrent disease. Prostate cancer, like other cancers, is a heterogeneous disease such that individualized/precision medicine is likely to benefit patients. Our data indicate that a subset of prostate cancer exhibits reduced expression of a protein (cGAS) known to be involved in the response of cells to viral or bacterial infection. Importantly, lower expression of cGAS is correlated with prostate cancer recurrence, suggesting that loss of cGAS reduces efficacy of therapy. Interestingly, low cGAS is associated with poor outcome in lung cancer as well. In this proposal, we present preliminary data strongly supporting novel tumor suppressor roles of cGAS in prostate cancer functioning in individual cancer cells. We will fully investigate the underlying regulatory mechanisms and biological effects of the loss of cGAS in prostate cancer, along with the initial exploration of therapeutic vulnerabilities associated with this dysregulated pathway. We are hopeful that our studies will enable new therapeutic options for prostate cancer patients, with potential relevance to a subset of lung cancer.
Cancers develop changes in their genes, as well as changes in parts of the cell that control genes. BCOR is a gene that regulates cells by controlling genes, and is changed in a wide range of cancers affecting the blood and organs. By studying a group of more than 20,000 patients with cancer, we saw that the type of BCOR mutation found in a cancer depends on the tissue in which the cancer arises, suggesting that BCOR may have a range of different roles. In patients with endometrial cancer, BCOR mutations are common, and affect a specific part of the gene. The first goal of our study is to describe the clinical impact of BCOR mutations in a large group of patients with endometrial carcinoma. The second goal is to understand how BCOR mutations affect the function and contribute to cancer in cells from different tissues.
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.
