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.
The overarching goal of research in my laboratory is to understand how cancer cells metastasize and spread to vital organs in the body, such as the lung, liver, bone and brain. In breast cancer patients, metastasis leads to death in over 40,000 women in the U.S. each year. The possibility of progression to stage IV, metastatic disease is a constant source of fear and anxiety, since 30% of patients eventually progress to metastasis and survival for these patients is very poor (<3 years). Despite its prevalence, metastasis is an incredibly complex biological process that is very challenging to study due to the limited availability of authentic model systems. My laboratory has developed an innovative new approach to study metastasis in high resolution, using cutting-edge new single-cell technologies to study how individual cancer cells spread in human patient tumor models of breast cancer. Using our approach, we have found that cancer cells use a specialized form of cellular metabolism in order to spread. In our proposed study, we will investigate why and how this form of metabolism promotes cancer cell spread, and we will explore the effectiveness of using metabolic inhibitors to prevent metastasis and fatality in cancer patients.
Funded by the Dick Vitale Pediatric Cancer Research Fund
Diffuse Intrinsic Pontine Gliomas (DIPGs) are heartbreakingly aggressive tumors of childhood for which no curative treatments currently exist. Our research is focusing on a gene called PPM1D which is commonly mutated in DIPGs. We are studying how these mutations cause the tumors to grow and are trying to find ways in which we can target them in new treatments for children with DIPG.
Funded by the Constellation Gold Network Distributors
Non-small cell lung cancer (NSCLC) is a leading cause of death worldwide. Many NSCLCs are caused by exposure to carcinogens, such as cigarette smoke, which cause changes to a cell’s DNA. These genetic changes can be detected by DNA sequencing methods. Next generation sequencing of tumors can provide clinicians, patients, and researchers with essential knowledge about the genes and proteins that cause and contribute to disease. Unfortunately, most human proteins (>95%) remain undrugged or inaccessible to labeling by FDA approved small molecules. Consequently, most cancer-associated proteins identified by DNA sequencing cannot be drugged. Therefore, we need new methods to identify druggable pockets in cancer-causing proteins. Our research develops such technology. In this study, we will develop a new approach to translate genetic changes into therapies. Our first step is to identify drug vulnerabilities that are specific to tumors. We will achieve this goal by combining next generation sequencing with new proteomics methods developed by our group. Next, we will synthesize drug-like molecules that can specifically label these tumor-associated proteins. Finally, we will determine how the protein targets of our compounds cause or contribute to cancer. Long-term, our studies will help guide the development of new precision therapies that will have fewer side effects and improved patient outcomes.
The term “metastasis” describes the spread of cancer cells from their original location in the body to nearby or distant organs. Almost 90% of all cancer deaths are because of metastasis. Unfortunately, this estimate has not changed in the last 50 years and our understanding of metastasis is limited. In order to effectively treat metastasis, we need to first understand them. Both cancers and their metastasis contain mutations in their DNA. Using our advanced algorithms, we can utilize these mutations to generate a tree that shows the evolution of a cancer in an individual cancer patient. On this tree, we can map the most important changes that can be used by doctors for making treatment decisions. In addition to using individual mutations, we can also use the patterns of all mutations in a cancer patient to pinpoint the processes that were active during evolution of the cancer. Some of these processes can be used as clocks to time the important changes found on the tree. Overall, we will create a high-definition timeline of the molecular events in the metastatic cancer of each individual cancer patient. The project will examine almost 2,000 cancer patients and increase our understanding of the events needed to transform a cancer to a metastasis. This knowledge is an essential step in providing patients with metastatic cancer with an informed and optimal cancer treatment.
Multiple myeloma is a cancer of the blood and is the second most frequently diagnosed blood cancer in the US. Every year, about 30,000 patients are newly diagnosed, and about 12,000 die from this cancer. The main symptoms include anemia, bone pain, kidney failure, and infections. The most recent treatments have improved patient survival from about 3.5 to 5 years. Unlike some other blood cancers, myeloma still cannot be cured. Thus, the development of new drugs and treatments is essential. The purpose of our study is to understand how an understudied class of genes, called long noncoding RNA genes (lncRNAs), participates in the development of multiple myeloma and may be used to develop entirely new treatments. Specifically, we propose innovative approaches to investigate a specific lncRNA gene, MALAT1 (metastasis-associated lung adenocarcinoma transcript 1) and how it functions in the repair of damaged DNA to promote the initiation and progression of multiple myeloma. We recently discovered that the MALAT1 gene is involved in an alternative DNA repair network that has seldom been studied in multiple myeloma. We believe that MALAT1 modulates the transition to advanced myeloma and myleoma that occurs outside the bone marrow. Our fundamental goal is to establish how MALAT1 regulates the repair of DNA damage and therefore its functional significance in multiple myeloma initiation and progression. This entirely novel knowledge will open new avenues for patient therapy and ultimately improve patient outcomes.
Funded by the Constellation Gold Network Distributors
Only a limited number of proteins are found in nature, and many of them have multiple different functions that clash with one another, which makes them poor drugs. There is a growing interest in engineering existing proteins or designing brand new proteins that are better than the ones in nature. Most current methods for protein design use a random approach. However, as our understanding of protein structure improves, we have an exciting chance to use structure to guide design. My lab applies new tools from biology and engineering to figure out the mechanisms that control protein behavior. We then use this information to discover and develop better drugs.
One of the biggest cancer breakthroughs is immunotherapy, which activates the patient’s own immune system to fight disease. My lab aims to bias the activity of immune proteins in order to achieve a targeted response against cancer. For more than twenty years, immune proteins such as cytokines and antibodies have served as powerful weapons in cancer treatment, but they are limited by issues such as drug resistance and harmful side effects. As a result, there is an unmet need to create new proteins that overcome these challenges. Building on our lab’s insights and platforms we have designed, we will make a new protein drugs that act through unique pathways to induce potent anti-cancer immune responses.
Funded by the Dick Vitale Gala in memory of Chad Carr
Cancer is the leading cause of disease-related death of children past infancy in North America. All cancers contain mutations in their DNA, but the causes of these mutations are usually not known. This gap in our knowledge negatively impacts patient care: It is difficult to predict how a tumor will change – how it will respond and whether it will come back – if one does not understand why or how it developed in the first place. Recently, our lab and others have shown that some childhood cancers contain a fingerprint which can be used to pinpoint what caused its mutations and when they developed. The identification of these fingerprints, or mutational signatures, is a rapidly evolving area of research that has benefited from new technologies, such as whole genome sequencing. This project will identify mutational signatures in aggressive childhood cancers. We will seek to understand whether cancer- causing mutations have common fingerprints, and if these can be used to select patients that would benefit from ongoing clinical trials.
Volunteer Grant funded by the 2018 V Foundation Wine Celebration in honor of John and Biserka Noval
Cancer is a leading global health concern. Until recently, cancer patients are normally treated with surgery, pharmaceutical reagents that can kill tumor cells (chemotherapy), and radiation (radiotherapy). In recent years, scientists and doctors have been trying to improve patients’ own immune function to combat cancer, known as immunotherapy. Cancer cells can fool the immune system by expressing some markers that can inhibit immune function. These markers are called “immune checkpoints”, including CTLA-4 and PD-1. Subsequently, blocking “immune checkpoints” with reagents (anti-CTLA-4 and anti-PD-1) could enhance immune function and result in impressive curative effects in some patients with cancer. Yet, a lot of patients do not respond to anti-CTLA-4 and anti-PD-1. In order to broaden the patient populations that can benefit from these novel reagents, we plan to change the metabolic features of the microenvironment that tumor cells live in. We hope doing this will improve the function of immune cells, which then causes non-responsive tumors to respond to anti-CTLA-4 and anti-PD-1 treatment. Our studies might also identify some markers that can help doctors in selecting the right patients for these therapies. Our long-term goal is to translate our findings from bench to bedside by designing clinical trials to test combination therapies, particularly in cancer patients that have been non-responsive to anti-CTLA-4 and anti-PD-1 therapies.
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.
