Funded in partnership with WWE in honor of Connor’s Cure
Hepatoblastoma (HB) is the most common cancer of the liver in children. Although usually very curable, some HBs have less than 20% survival. About 80% of these have changes in a protein known as b-catenin. Many also show abnormal regulation of another protein called YAP. Together, these are the most common changes in HB. Mice develop HB if a mutant form of b-catenin, termed D(90) and a mutant form of YAP known as YAPS127Aare expressed together in the liver although neither one alone causes tumors. 5-10% of HBs also contain mutations in a third protein, NFE2L2, that normally prevents certain types of DNA damage. In initialstudies, NFE2L2 mutants sped up tumor growth in response toD(90)+YAPS127A. Unexpectedly, NFE2L2 mutants caused tumors when present in livers with eitherD(90) or YAPS127A. Thus, any two combinations of thesemutations cause cancer. This research will ask exactly how each pair of mutant proteins alters tumor growth. It will also identify the small number of common changes that underlie these tumors. This has previously been impossible because the differences between normal livers and tumors is so large. Identifying the genes shared by different mutant combinations should make this easier. Our proposal is innovative because it will find the most important changes that cause HB. It is translationally important because knowing these changed genes may uncover new ways to treat HB and other pediatric and adult cancers.
Funded in partnership with Miami Dolphins Foundation
It is estimated that 1 in 8 women will be diagnosed with breast cancer in the US. During the last decades, breast cancer survival rates have greatly improved, mainly due to factors such as earlier detection and a better understanding of the disease. There are at least five different type of breast cancer. In this proposal, we will investigate one of the breast cancer subtypes, called estrogen receptor positive (ER+) breast cancer. ER+ breast cancer needs the estrogen to grow.Estrogen is a hormone that is important for sexual and reproductive development, mainly in women. ER+ breast canceraccounts for 70% of breast cancers and is typically treated with drugs designed to slow or stop the growth of cancer that uses estrogen to develop. Although thistype of therapy has been shown to reduce the risk of relapse and death from breast cancer,one third of patients develop resistance. This resultsin the spreading of cancer cells to other organs, known as metastasis. Thus, there is a critical need for identifying new treatments for patients who develop resistance to current therapies. The focus of this proposal is to understand the mechanisms of resistance to therapy and to overcome resistance by using a novel therapeutic approach. This is the next step towards our overarching goal, which is the identification of new therapeutic opportunities for the treatment of patients with aggressive breast cancer.
Funded in partnership with the Kansas City Chiefs Football Club
The immune system can destroy cancer cells. This is being taken advantage of in cancer therapy, withscientists trying to find ways to activate the immune system to better kill cancer cells. One therapy involves theinfusion of immune cells named natural killer (NK) cells. This therapy works well for some types of cancers.However, there has been limited success with this therapy against most tumors. The ultimate goal of our research is to increase the ability of this therapy to work against more cancers. One method proposed formaking NK cells better at killing cancer cells is treating the cells with activating signals that are termed IL-12, IL-15, and IL-18. We show that this makes the NK cells express proteins that affects the ability of the cells to killcancer cells.This leads us to think that IL-12,15, and18 treatmentalters NK cells in a way that can be good for the treatment of some, but bad for other, types of cancer.This is of highconcern because IL-12,15,18 treatment is proposed as a way to enhance NK cell treatment of cancers and isbeing tested in patients. Therefore, it is critical we determine how IL-12,15,18-treated NK cells affect the growth of different types of cancer. Here we propose to determine how IL-12,15,18-treatment, and the proteins this treatment induces on NK cells, alters the ability of NK cells to kill cancer in mouse models.
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.
Funded in partnership with the Morris Animal Foundation and the Wine Celebration Fund-A-Need
In 2012, Morris Animal Foundation launched its Golden Retriever Lifetime Study primarily to explore the risk factors related to cancer in golden retrievers. The Study has been following 3,044 dogs throughout their lives, collecting wide-ranging data on each animal each year, including environmental exposures, behavior, medical diagnoses, medications, diet and more. Golden retrievers were selected for this study because they are diagnosed with cancer at a much higher rate than most other breeds of dogs, and some of the most common cancers in golden retrievers are closely related to common human cancers.
This grant relates to genomics of our enrolled Study dogs. We will first test DNA samples from all of the dogs. We will be looking for small variations in hundreds of thousands of places along the DNA strands. Some variations may imply that a dog has a greater risk of a certain cancer type or one of the other diseases we are documenting. Similar studies are done for humans, but the advantage in dogs is that such information might ultimately be used in breeding programs to reduce the occurrence of cancer in the first place.
A second aspect of the grant will focus on biopsy specimens. We receive biopsy specimens from many of the cancers diagnosed in our Study dogs. We will be conducting a very detailed analysis of DNA, called sequencing, in these cancer tissues. Cancers occur due to changes in the DNA, called mutations. This study will allow us to determine which mutations are occurring in certain cancers that have similarity with those occurring in human patients. These include lymphoma (a cancer of white blood cells), osteosarcoma (bone cancer), and hemangiosarcoma (cancer of blood vessels). This information may lead to further studies on how to prevent and treat these cancers in both dogs and humans.
Funded in partnership with the Morris Animal Foundation and the Wine Celebration Fund-A-Need
In 2012, Morris Animal Foundation launched the Golden Retriever Lifetime Study primarily to explore the risk factors related to cancer in golden retrievers. The Study has been following 3,044 dogs throughout their lives, collecting wide-ranging data on each animal each year, including environmental exposures, behavior, medical diagnoses, medications, diet and more. Golden retrievers were selected for this study because they are diagnosed with cancer at a much higher rate than most other breeds of dogs, and some of the most common cancers in golden retrievers are closely related to common human cancers.
The data being collected by the Golden Retriever Lifetime Study is freely available for academic research via the Morris Animal Foundation Data Commons. The goal of the current project is to augment the Data Commons with high-resolution genotype data on each of the dogs and, eventually, complete DNA sequence data on all of the dogs diagnosed with cancer, along with a suitable number of other dogs as controls. As the genotyping and sequencing is completed, Morris Animal Foundation will perform preliminary data validation and analysis, and then incorporate the data into the Data Commons, where it will be available to everyone with an account. This will enable researchers from institutions around the world to participate with us in the effort better understand canine cancer as well as inform human cancer research.
Morris Animal Foundation Data Commons accounts can be requested by anyone involved in academic research by completing the registration form on the Data Commons website.
All cancer patients should have the opportunity to get very good care through research studies. Research studies are important to make cancer treatments and survival from cancer better but very few people of color are treated on cancer research studies called clinical trials. One way to solve this problem is to use specially trained staff to help cancer patients better understand clinical trials. These staff are called patient navigators. In this project, we will use patient navigators to teach and support patients asked to be in a cancer research study. These navigators will work as a team to make sure that all African Americans who receive care at the Cancer Center are considered for a clinical trial. In order for the patient navigator to know which patients may be fit to participate in research, we will use information from the medical record to create a list of patients that could be asked about their interest to get treatment with a clinical trial. The patient navigator will use this list to contact patients and will teach patients about clinical trials and connect patients to finance counselors, social workers and other helpful community services as needed. To understand if the project is a success, we will compare the total number of patients, by race, treated on a cancer research study before and after the project.
Funded in partnership with The Leukemia & Lymphoma Society’s PedAL Initiative and the Wine Celebration Fund-A-Need
Acute myeloid leukemia is a cancer of bone marrow cells. It can be difficult to treat, particularly in young patients. The disease can differ from one patient to another, depending on the kinds of mutations that are found in the cancer cell. Different mutations may respond to different treatments.
Dogs also develop acute leukemia. In this species the outcomes are dismal, with most dogs being euthanized within days of the diagnosis because of poor quality of life. Currently available chemotherapy is ineffective in this species.
In this project we will sequence DNA and RNA from 100 cases of naturally occurring acute leukemias in pet dogs. Our goal is to find mutations and gene expression patterns shared between dogs and people. Once these shared features are identified, new treatments can be devised which can be tested first in dogs, and if successful, translated to humans. This approach offers a chance at better therapies in both species.
Clinical trials offer a path to cure for cancer patients by testing methods to prevent, find or treat many types of illness. Yet, patient access to clinical trials varies; rural areas have limited health care services. Duke University has a wealth of clinical trials for patients with cancer. The goal of this effort is to increase the clinical trials available from Duke to the community. The clinical trials will focus on specific ethnic groups in specific locations. Two types of clinical trials will be the focus: Uncommon cancers– such as blood-based cancers, or cancers that have different effects on specific races – such as prostate.
Duke doctors with special knowledge in Prostate Cancer and blood cancers will go to specific clinics. The Duke doctors will talk with doctors and nurses in the community about patient cases. We will test to see if rural clinics can use central storage for test results from tumors. Central storage will let us match test results from tumors to available clinical trials.
Our team wants to include patients in our effort to improve knowledge about clinical trials. We want to help make them aware that clinical trials are available. A committee that includes patients will help guide the creation of educational tools for patients.
Prostate cancer afflicts one in seven men and is their second leading cause of death, justifying development of more effective therapies. Prostate cancer depends on testosterone binding to and activating the androgen receptor (AR), which in turn promotes the growth of prostate cancer. Current therapies for prostate cancer are aimed at reducing AR activity, either by blocking the production of testosterone or through agents which compete with testosterone for binding to the AR. Our approach is depleting cancer cells of the AR protein by promoting its degradation. We will accomplish this by manipulating the pathways (either genetically or with drugs) which control protein degradation. Our preliminary data show that we can promote degradation of the AR in cells in test tubes. In this proposal we will test if we can promote AR degradation in mouse models of prostate cancer.
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