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 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.
Many cancers are treated with radiation therapy. Some cancers types are especially hard to treat. One type of cancer that affects the lungs and throat is only cured in about half of cases. Even when drug treatments are added to the radiation therapy, cure rates are not much improved. Also, adding drugs to radiation therapy can make the treatment hard for patients to tolerate. New treatment approaches are needed for these patients.
One new approach that is showing promising results is to give refined treatments that are more precisely targeted to each patient’s cancer. This approach is called Precision Medicine. Precision Medicine has not been used much for the cancer type that affects the lungs and throat. Also, Precision Medicine has not yet been used for radiation therapy. Instead, the standard treatment for these patients continues to be a one-size-fits-all approach.
We expect that the standard one-size-fits-all treatment approach could be replaced by Precision Medicine. The objective of our research is to develop new Precision Medicine approaches for the cancer type that affects the lungs and throat for use with radiation therapy. These new treatments could someday lead to higher cure rates and tolerability of treatment. If successful, our research will lead to new clinical trials that will test these new treatment approaches in cancer patients.
Breast cancer is the most common type of cancer in women worldwide. Metastatic disease is incurable and causes 90% of breast cancer-related deaths. Current treatments for breast cancer help patients live longer, but they have no effect once the tumor is in the brain. Moreover, by prolonging survival they increase the risk of brain metastasis over time.
Primary breast tumors secrete factors that travel through the blood and facilitate seeding and growth of new distant tumors by inducing changes in the structure of other organs. The proposed research will look at how regulatory T (Treg) cells, a type of immune cells heavily present in primary tumors, support changes in the brain tissue that allow brain metastasis to develop. To model this, we will utilize genetically engineered mouse models and surgical manipulations like the ones occurring in human breast cancer patients to investigate how the presence of regulatory T cell affect brain metastasis formation over time. Specifically, we will assess the changes in cell composition and structure of the brain tissue before metastasis develops in mice with and without Treg cells. In addition, we will evaluate changes in blood circulating factors, and establish the requirement of cells from the bone marrow and specific cytokines for the remodeling of the brain. By learning more about what happens to the brain tissue before metastases form, we hope to improve our chances of developing therapeutic strategies to prevent them.
Lung cancers are often driven by genetic changes. The focus of my research is on a type of lung cancer that is driven by changes in the EGFR gene. This type of lung cancer often occurs in younger patients who are non-smokers. New medications can target these changes. This has allowed patients to live longer. However, patients are almost never cured of their disease. My goal is to understand why responses to these EGFR targeted treatments are almost never curative. Then I will work to identify new medications that can be used together with EGFR inhibitors. This may allow patients to live longer. I will accomplish this goal by identifying all of the genetic changes present in patients’ tumors. This will allow us to understand which ones may be allowing cancer cells to survive. I will also assess tumors for other changes that occur within cancer cells. In addition, I will look at the immune cells that are in the tumor. To summarize, the goal of this research is to identify new combination therapy strategies that can improve the depth and duration of response to EGFR targeted therapies, allowing patients with this deadly disease to live longer.
Funded in partnership with the SAGERSTRONG Foundation in memory of Craig Sager
There are trillions of bacteria, viruses and fungi inside each and every human. We call this the microbiome. Scientists have found that the microbiome can change how cancer grows and how people respond to cancer therapies. Our lab wants to make the lives of cancer patients better by improving their microbiomes. The usual ways to change the microbiome are through diet, antibiotics, and by eating live bacteria in food. An example of a food with live bacteria is active culture yogurt. We are doing an experiment to see if a special type of fiber can improve the human microbiome. This fiber is digested by specific bacteria in the gut. When it is digested, it is turned into molecules that control the human immune system. We are giving cancer patients this fiber to see if we can increase these immune system-controlling molecules. If this works, we will prevent the immune system from doing harm in cancer patients. We hope to help patients like those who get blood and marrow transplants for treatment of leukemia or lymphoma. Once we understand how these fibers and our microbes change the immune system, we can figure out precise ways to use this knowledge to make the immune system work better. For example, we may be able to make exciting new cancer therapies, like immunotherapy, work better.
Age is the greatest risk factor for breast cancer. About 80% of all breast cancers occur in women older than age 50. Aging is associated with tissue changes as well as changes in the genes that are expressed in breast cells. However, the age-related molecular and cellular mechanisms that underlie these changes and contribute to breast cancer development remains poorly understood. Our lab studies a mechanism by which genes are read to produce different proteins, called RNA splicing. RNA splicing can generate proteins with different functions from a single gene. We previously discovered that this process is altered in human tumors and leads to breast cancer. Additionally, changes in RNA splicing also occur in healthy aging. Here we will test the hypothesis that (1) changes in RNA splicing occur in the mammary tissue with age, and (2) that these splicing changes prime the breast for tumor formation. Our research findings may provide biomarkers of breast cancer risk before the tumor develops. Our ultimate goal is to identify novel strategies for early breast cancer detection, early intervention, and prevention.
