Funded by 2019 Kay Yow Cancer Fund Final Four Research Award
Cancer in the ovaries is an aggressive and deadly disease with limited treatment choices. A crippled protective immune system is commonly found in patients with ovarian cancer and limits the effect of multiple treatments. We recently described a new therapy based on the transfer of immune T cells engineered to spot and kill ovarian cancer cells. These therapeutic cells are referred as FSH-CER T cells. Here, we propose a plan to boost the effects of FSH-CER T cells by promoting the growth of T cell subsets with a higher capacity to eliminate tumors. This will be done by the inhibition of key drivers of cellular stress. Thus, our data will set the basis for a therapy to efficiently treat ovarian cancer patients.
Funded in partnership with WWE in honor of Connor’s Cure
Brain cancer is now the leading cause of cancer deaths in children. A tumor known as high-grade glioma (HGG) is the deadliest type. Children with HGG are treated with surgery, chemotherapy, and radiation. They often enroll in clinical trials to try new treatments. Unfortunately, most children die within two years of diagnosis. Part of the problem is that HGG tumors develop ways to resist the effects of treatments. Our recent work using promising new glioma treatments has identified a pattern of steps that glioma cells use to develop treatment resistance. Using state-of-the-art genetic testing, we saw how HGGs at first responded to new therapies but then became resistant. Resistant HGGs showed increased levels of a protein called QPRT, which can use energy metabolites like NAD+ to protect cancer cells from the therapy designed to kill them. This suggests that by stopping the protein function, we could overcome treatment resistance. We want to achieve two aims: First: to see if QPRT is active in other commonly used treatments for HGG, and also if recurring childhood HGGs typically show high QPRT levels. Second, using tumor tissue that we cultured in the lab, we identified a drug that inhibits the NAD+ pathway and reverses treatment resistance. We want to test this drug in an animal model of treatment-resistant HGG to see if it can prolong survival. Together these aims would reveal a way that HGGs resist treatment and potentially show how a drug could block this action to overcome treatment resistance in these tumors.
Funded by the V Foundation’s Virginia Vine event, in honor of WWE Connor’s Cure
Cure rates for children with cancer are improving, but cancer still comes back for many kids after finishing therapy. When cancer comes back it is more difficult to cure, and new treatments are needed to help these patients. The best way to develop new treatments is to treat patients with new therapies while collecting detailed information about how they tolerate the treatment and if it gets rid of their cancer – this is called being treated on a clinical trial, a research study designed to learn about how new treatments work for patients. These studies that involve new treatments are usually only offered at large hospitals that are connected to medical schools, so many patients are sent away from their homes to receive these treatments. Others choose to stay closer to home and not receive the newest therapies for their cancer. Often, there are research studies closer to home than their doctors realize. Getting this information to the doctors in our region would help make sure patients receive the newest therapies for their cancers while staying close to home. This grant would allow us to travel to nearby medical practices to tell the doctors about the new therapies that we offer at UVA as part of clinical trials, especially treatments that are being developed that allow the patient’s own immune system fight their cancer (called “immunotherapy”). Spreading this information will hopefully increase the number of patients that are treated on these research studies, and help cure more kids of their cancer.
Funded by the V Foundation’s Virginia Vine event, in honor of WWE Connor’s Cure
Cancer in children is rare, accounting for less than 1% of all cancer cases in the USA. Clinical trials are used to determine the most effective and safest treatment for a disease and are commonly used in cancer treatment for children, adolescents, and young adults. The main reason that children are not enrolled on clinical trials is that there is not an open trial available. However, some nationally available trials could be opened faster when needed in local hospitals or cancer centers. Currently, the process is quite complicated and involves many steps. Our goal is to develop a “library” of available clinical trials that could be activated quickly on an as needed basis for children with rare tumors or with a cancer that does not respond to standard treatment. We will examine the barriers to rapid activation, educate the committees that are involved in clinical trial activation at our institution about the uniqueness of childhood cancer, and come up with a process for rapid clinical trial activation for childhood cancer at the Massey Cancer Center.
The Duke Cancer Institute and the College of Veterinary Medicine at N.C. State University formed a Comparative Oncology Consortium (COC), taking advantage of their expertise and national leadership in their respective disciplines and their geographic proximity. The goals are to collaborate in pre-clinical and clinical cancer research activities in order to advance our understanding of both cancer causation (a high incidence of specific cancers in specific dog breeds provides opportunities to identify new cancer susceptibility genes and environmental factors in cancer causation) and of behaviors and genetics of specific tumor types, as well as to coordinate clinical trials in humans and canines so that novel therapies can be tested in both settings, with information gained in one setting informing the other. In addition to response outcomes of these cancer therapies, the ability to use biomarkers and pharmacology in the canine models can be a novel addition to the characterization of these new cancer therapies and these insights could result in significant enhancements of clinical trial designs (including dosing, scheduling, and combination therapies) when these treatments are tested in human clinical trials. Cost savings and improved clinical trials design would help encourage pharmaceutical companies to use the canine models as part of the assessment process and would benefit the canine patients by giving them access to these novel therapies.
Project 1: My research interest is cancer genetics with an emphasis on clinically relevant questions that will improve our understanding of the cancer genetics of clinical phenotype and simultaneously improve patient care in oncology. I have extensive bench research experience in the fields of genome sequencing technology development, human genetic analysis through human genome sequencing and molecular assay development. My research benefits from the various innovations in genomic and genetic technologies that my group has developed.
Project 2: Based on a series of recent discoveries using cutting edge tools in genomics, we have (1) identified a new targeted way of treating metastatic gastric cancer and (2) pioneered a new way of determining how gastric cancer cells control normal cells in the surrounding stomach tissue.
Our overall goal for this project is to use single cell genomic sequencing to identify new drug targets by analyzing primary gastric cancers from metastatic patients.
Project 3: Based on a series of recent discoveries using cutting edge tools in genomics, we have (1) identified a new targeted way of treating metastatic gastric cancer and (2) pioneered a new way of determining how gastric cancer cells control normal cells in the surrounding stomach tissue.
Our overall goal for this project is to determine if our new discovery of a drug combination will improve the treatment of metastatic gastric cancers with the FGFR2 defect.
Funded by the V Foundation’s Virginia Vine event, in honor of WWE Connor’s Cure
Our grant aims to develop drugs for altered forms of the protein MLL which arise in pediatric leukemia. Patients with leukemia harboring altered forms of MLL have very poor survival, highlighting the need for new approaches to treat these patients. The altered MLL proteins are highly dependent on the ability of one part of the protein to bind to DNA. We are developing drugs to block this binding. Our initial results support that this approach could be highly effective for treating this type of leukemia. Since this is a new way to treat the leukemia, it has the potential to be more effective than currently used drugs as well as less toxic. In addition, since this is a very different approach from existing drugs, it is likely that combinations of this new drug with existing drugs will provide unique benefits.
Funded in partnership with the Goldberg Family Foundation and in collaboration with the Gray Foundation
Individuals with BRCA1 or BRCA2 mutations have an increased risk of developing breast, ovarian, pancreas, prostate and other types of cancer. Tumors arising in these individuals are often sensitive to PARP inhibitors (PARPi) and this class of drugs has shown remarkable success in the treatment of BRCA1 and BRCA2-mutant tumors. Despite these successes, tumors frequently become resistant to therapy. Using functional genomic approaches, we will investigate mechanisms of resistance and identify novel genetic vulnerabilities that can be exploited by PARPi treatment. We will also investigate the immune response to BRCA-mutant tumors and explore ways to improve the ability of immune cells to recognize and kill these tumors. The ultimate goal of these studies is to improve outcomes for patients with BRCA-mutant tumors and to identify new groups of patients that can benefit from PARPi.
Supported by Bristol-Myers Squibb through the Robin Roberts Cancer Thrivership Fund
People who have been treated for cancer are not only at risk of cancer returning, but also at risk of long term side effects of their treatments some of which may threaten their life, including heart disease and other cancers. Medical teams are always searching for new ways to identify and reduce these risks.Some people will develop changes in their blood cells called “Clonal Hematopoiesis”(CH) and people with these changes have recently been found to be at higher risk of developing serious problems such as cancer and heart attacks and dying. CH is found more in older than younger people and more commonly in people who have been treated for cancer. We don’t know how common CH is in cancer survivors, who is at risk, when it develops and when and if we should be looking for it. But we are finding it more commonly with genetic tests that are being done as a part of their care. Our team hopes to provide answers to these questions by looking for CH in a group of women who were treated for breast cancer at a young age and agreed to give us blood samples and let us follow them over time. We will do special testing to find CH in their stored blood and see how it is different in different women, and changes over time. We will also ask them how they might feel about learning about CH results if they had CH, how learning about these risks that might affect them, and what they might need to support them best to help them to manage these risks. We hope this research leads to findings that can be used to understand this problem better and to improve how we take care of cancer survivors both now and in the future.
Supported by Bristol-Myers Squibb through the Robin Roberts Cancer Thrivership Fund
Leukemias represent cancers of the blood and are caused by genetic changes (mutations) in our blood cell that drive uncontrolled cell growth. Cancer survivors are more likely to develop leukemia than the general population. Traditionally this was thought to be a consequence of toxicity from the treatments used to fight their cancer, which leads to the development of therapy-related myeloid neoplasm (tMN) one of the most deadly and challenging to treat cancers. However recent studies show that leukemia associated mutations can be found many years before cancer diagnosis and interestingly, these blood mutations can also be seen in healthy people who never develop leukemia. This is phenomenon is called clonal hematopoiesis (CH). Our group has shown that CH is frequent in cancer patients and we find that cancer treatment may promote growth of cells carrying such mutations. To understand the effects of cancer treatment in patients that carry such mutations and how this dictates subsequent progression to leukemia, we propose to study a total of 45,000 cancer patients at time of cancer diagnosis. This will identify individuals with CH at time of diagnosis. We will then follow up patients and study the effects of oncologic therapy to analyzed for the presence of CH and study the effects of distinct cancer treatments on CH. Our study will help us understand tMN and guide the development of interventions to prevent tMN.
