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.
Funded in partnership with Adenoid Cystic Carcinoma Research Foundation (ACCRF)
We recently found that retinoic acid treatment reduces the growth of a salivary gland tumor. The retinoic acid has the ability to shut down the cause of the cancer which is due to the overactivity of a gene called c-myb. Retinoic Acid has been successfully given to patients with a rare type of leukemia and we plan to use the same doses as the leukemia patients. We will examine whether the retinoic acid is active in the tumor and whether the growth of the tumor is reduced. Our studies have the possibility of finding the first treatment for this metastatic tumor.
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.
Year one is partially funded by UNICO in memory of Toni Alongi
Survivors of childhood leukemia (ALL) who are treated with chemotherapy develop poor cognitive skills (e.g. attention, speed of thinking, reasoning). These poor cognitive skills cause problems with school, work and peer interactions. The survivors also display abnormalities on brain imaging. We demonstrated that fluid collected during a spinal tap (i.e. cerebrospinal fluid [CSF]) contained markers of brain injury. However, our initial study was too focused on specific brain cells. We could not identify the cause of the brain injury. Thus, we want to conduct another study to examine many more protein markers before and after chemotherapy treatment.
We will use an advanced process to identify over 4,000 proteins in the CSF. This will permit us to determine the cause of the brain injury. We will compare the proteins to sex and age of the survivors. We will also compare the proteins to the treatments the survivors got. Finally, we will compare the change in proteins to brain imaging and cognitive testing.
CSF samples from a recently completed trial have been collected and frozenat −80°C so they will not decay. The brain imaging and cognitive testing is currently being completed as part of an institutionally funded protocol. For the current project, we will process the CSF samples and link them to adverse events and clinical outcomes.
With this comprehensive approach, we will identify which survivors are at greatest risk, and identify targets to prevent brain injury in future clinical trials.
Supported by Bristol-Myers Squibb through the Robin Roberts Cancer Thrivership Fund
Aromatase inhibitors (AIs) are important drugs for treating breast cancer. These drugs lower estrogen levels and reduce the chance that a woman will die from cancer. However, about one in five patients stops taking the drug early because of aggravating muscle and joint pain. Stopping the drug too soon can increase her risk of her cancer coming back. We do not know why women develop this pain, but it might be due to very low estrogen levels. We also do not know how to prevent the pain. Oxylipins are fat particles in the body that can increase or decrease pain. We believe that when a woman is treated with medicine that lowers her estrogen levels, that leads to more fats that cause pain. By also taking omega-3 pills, we believe that women instead will have more fats that decrease pain. This will allow her to continue to take the AI medication. To address this question, women who are starting to take an AI will also take either omega-3 pills or olive oil pills. We will ask if they develop pain and also check the levels of fats in their blood. Through this study we will find out if omega-3 pills prevent this side effect, and will learn more about how the AI medicine causes the pain. Knowing more about why women get this bothersome pain and how to prevent it will allow doctors to better treat patients and will allow more women to continue taking this life saving medication.
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