Although childhood cancer survival rates have improved over the past 40 years, pediatric acute myeloid leukemia (AML) is still very difficult to treat successfully. This is partially because the immune system has a hard time recognizing and killing AML cells. Though white blood cells usually fight infections or cancer, certain types of “tumor-permissive” white blood cells (APCs) make it easier for cancer to escape being recognized by the immune system. These tumor-permissive APCs send out signals to other immune cells telling them to relax and not kill leukemia cells. Our research goal is to find ways to make these APCs stop sending tumor-permissive signals, so that the immune system can recognize AML cells better and get rid of the leukemia. Specifically, we found that APCs use a protein called MerTK to send tumor-permissive signals to other immune cells. When we block MerTK using a new orally-active drug, APCs stop sending tumor-permissive signals and instead, start sending new signals that tell other immune cells to fight leukemia. MerTK drugs are headed to clinical trials for their anti-cancer effects; our research demonstrates that these drugs could also be used to boost the immune system against cancer. With this grant, we will investigate the cellular steps involved in blocking MerTK, so that we can determine how to use MerTK inhibitors most effectively to treat pediatric patients with AML. We hope to show that this novel therapy will help improve pediatric AML survival rates and patient’s quality of life.
There is much controversy about the best age to begin mammograms (age 40 or 50?), and how often to do them to improve women’s health. National mammogram guidelines from various organizations give differing recommendations, causing much confusion for women and their health care providers. The University of California and the Sanford Health System (in South Dakota) launched the Wisdom Study to try to come up with a better way to help women determine what mammogram schedule is best for them.
The Wisdom Study compares annual screening to a personalized screening approach. Women in the personalized screening arm of the study receive a screening recommendation based on their individual risk factors (age, personal and family history, genetic risk factors, and breast density). We are comparing the two strategies to determine if personalized screening is as safe as annual screening, as assessed by no increase in diagnosis of Stage 2B breast tumors, and if it will reduce false-positive results and over diagnosis. We will also determine if personalized screening is readily accepted by women and if knowledge of their own risk and the reason for less screening will reduce or at least not increase anxiety about breast cancer. If the trial is successful, we anticipate benefits to women of screening age will include: 1) fewer women suffering from anxiety and stress of false positive mammograms and unnecessary biopsies; and 2) women gaining a realistic understanding of their personal risk of breast cancer, which may reduce general worry about breast cancer.
Funded in partnership with the Lung Cancer Initiative of North Carolina, utilizing Stuart Scott Memorial Cancer Fund matching funds, and the Richard Jones Fund for lung cancer
Lung cancer treatment has dramatically changed, particularly with the introduction of immunotherapies aimed at jump starting a patient’s immune system to fight cancer. Along with the development of new treatments, biomarkers have become increasingly important to disease sub-typing and evaluation. EGFR, ALK, and ROS1 are genes that can be mutated in patients with non-small cell lung cancer and serve as biomarkers. An individual’s tumor may have one or many mutations. The mutational landscape of the tumor has been shown to be an important determinant of response to immunotherapy. PD-L1 also serves as a biomarker, but there have been mixed results as to whether PD-L1 is appropriate for selecting immunotherapy treatment. Microsatellite instability (MSI) and mismatch repair (MMR) are new markers and may also predict response to therapy. Combinations of new and existing biomarkers may be better indicators of response to immunotherapies.
Many factors may contribute to the complex makeup of a patient’s immune response and each patient’s response may differ. Factors that may influence response include the patient’s own baseline immune landscape, age, gender, race, or environment.
Assessing biomarkers from patient’s blood and tumor samples may guide immunotherapy selection and treatment duration to optimize overall patient benefit. This study will assess the predictive utility of our blood immune response test to select patients appropriate for immunotherapy, as well as manage treatment over time. Of importance, this study will assess samples across patient populations, including African Americans, longitudinally and will evaluate differences in immune landscapes and how biomarkers may determine treatment.
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.
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.
V Scholar Plus Award – extended funding for exceptional V Scholars
Our research is important because we study a new uncharted realm of gene expression in cancer call mRNA translation. This significantly understudied field is poised to reveal new insights into what makes cancer so difficult to treat and identify completely new ways to treat them. Our laboratory has developed new technologies to study this process in cancer. For example, we specifically focus on late stage prostate cancer which leads to approximately 26,000 deaths per year in the United States. Through the generous support of the V Foundation, we have developed a tool box of advanced staged prostate cancer models and have discovered that mRNA translation plays a key role in this disease. Furthermore, we have developed new sequencing based technologies to study the parts of the human genome which regulate mRNA translation in cancer. Importantly, we are rapidly discovering that our work applies not only to prostate cancer, but to all human malignancies. Ultimately, we aim to develop new drugs to target mRNA translation. If we are successful we will break open completely new ways to think about and treat incurable cancers.
V Scholar Plus Award – extended funding for exceptional V Scholars
Breast cancer is the most common cancer in women. Despite advances in understanding how breast cancer develops, this has not translated into better therapies. The majority of breast cancers are positive for hormone receptors, such as the estrogen and progesterone receptor (PR), and are dependent on these receptors and their hormone ligands (estrogen and progesterone) for growth. However, as tumors progress they become hormone-independent, meaning they grow in the absence of hormones normally required for cell growth, perhaps due to unregulated hormone receptors. It was recently shown that women who were taking hormone replacement therapy that included progesterone had an increased risk of developing breast cancer, underscoring the importance of studying PR in breast cancer. Understanding PR action in the context of breast cancer is important to the development of better therapies.
PR is required during normal breast development and pregnancy, activating genes in the nucleus that stimulate cell growth. Recently, we identified that PR also regulates genes that drive inflammation, a normal cellular process that can function uncontrollably in cancer, generating mutations that may drive cancer growth. Decreasing inflammation has been shown to reduce the risk of developing breast cancer. The objective of the proposed experiments is to determine how PR regulates genes involved in inflammation, and if PR-dependent inflammation can be detected, and eventually blocked, in breast cancer. Understanding how PR regulates inflammation could lead to the development of a new area of therapies for breast cancer, combining currently existing hormone-based therapies with treatment aimed at reducing inflammation
African Americans often do not take part in research. To raise the community’s knowledge about breast cancer research, we will work with trusted members of the community through our Community Ambassador Training (CAT) program. We will craft a training about the value of research and what it means to take part in research. The training will build on their current knowledge through activities that highlight breast cancer. Once trained, Community Ambassadors will take the information to the community spreading the word about the value of research.
Almost all of our knowledge about cancer and medicine is about the proteins that are encoded by only 2% of human genome (the DNA that is contained in our chromosomes and carries the program for making our cells and controlling them). However, in the recent years the scientific world has been transformed by the revelation that significant parts of our genome are expressed as molecules called long noncoding RNAs (lncRNAs), which do not code any proteins, but nevertheless play critical roles in normal and diseased conditions. LncRNAs are critical for gliomas, reveal novel molecular mechanisms of cancer progression and are new targets for therapy. LncRNAs are expressed in different subtypes of gliomas at higher or lower levels compared to the surrounding normal brain, and this makes them useful as novel markers that may help in diagnosis and in predicting outcome for the patient. So far only a few lncRNAs associated with gliomas have been functionally characterized, and even less is known about their mechanisms of action and their usefulness as markers. In this collaboration between Drs. Dutta and Abounader we will focus on novel lncRNAs- H19, LINC00152 and several TUCRs, that are differentially expressed in gliomas and that influence the way a glioma behaves. Our objective is to determine the mechanisms by which these RNAs affect glioma biology, get a comprehensive catalog of all TUCRs that are differently expressed in gliomas and to determine whether targeting these lncRNAs will be therapeutic for gliomas.
Treatment for children with relapsed leukemia has been transformed by the use of chimeric antigen T-cells (CAR-T), which use a patient’s own immune cells after they’ve been engineered to kill leukemia cells by recognizing specific proteins on cells. Yet, about a third of children will again suffer relapse after CAR-T cell treatment when the leukemia cells stop expressing the target protein on the surface of the cell. This makes the leukemia cell invisible to the CAR-T cells and blunts eradiation of the leukemia. This occurs when the leukemia cells express alternative forms of the target protein. It is not well understood if these alternative forms only occur after pressure of the CAR-T treatment or if they exist already within the patient’s cells and are only revealed after CAR-T treatment. There is suggestion that healthy cells express the alternative protein forms as well. There is need to better understand what healthy cells express the variant protein forms, what their role is in normal cell biology and if leukemia cells, without pressure of CAR-T targeting express these proteins. We will use novel single-cell technologies to examine healthy bone marrow cells and diagnostic leukemia cells to determine if these cells express the variant proteins and to what extent. We will examine how these variant proteins help cells to survive. Finally, we will examine samples from patients treated with CAR-T cells to determine if these cells exist before receiving CAR-T treatment and how the treatment favors emergence of resistant cells expressing variant proteins.
