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.
Participation in breast clinical trials ranges from about a low of 0.5% to a high of 2-3% in patients with breast cancer. The majority of these trials have involved surgery, chemotherapy, and radiation all with substantial side effects but even when the safety profile is minimal these trials have not appealed to patients. More recently it has become clear that the immune response plays a large part in determining how well someone does when diagnosed with breast cancer. It is even possible now to utilize that immune response in the blood to predict response to therapy and predict recurrence. This means that the immune response can be used to predict cancer development, predict response to therapy and possibly improve outcomes by manipulating the immune response using immune stimulants, vaccines, cell therapies, and adoptive cell strategies to bolster the immune response to prevent recurrence. The purpose of this project is to develop an educational program in the burgeoning field of breast immunoncology for breast cancer oncologists and other physicians, patient advocates, patients and care givers to improve awareness about the immune response in breast cancer and how we can use the immune response to optimize our current therapies and where additional immune manipulations will improve outcomes. Our goal is to increase awareness about clinical trials in breast immunotherapy that ultimately increase patient accrual on studies and more rapidly move these promising modalities to clinically useful treatments for all patients with breast cancer.
The purpose of our project is to create educational materials that can be used to increase the awareness of a minority populations of the benefits of cancer clinical trials. Our expectation is that an increased awareness will help make cancer clinical trials more understandable and will increase the likelihood that they will be considered as an excellent option for minority cancer patients needing therapy.
In order to create the educational materials, we plan to bring together a multidisciplinary group of cancer providers which will include physicians, nurses, social workers, and cancer research coordinators. This group will help develop the educational information. In addition, we will also bring together minority cancer patients to advise us as to potential concerns or barriers that minority patients may have in regards to clinical trials. In this way we will be able to address those concerns in our educational materials.
Utilizing the information that we will obtain from these activities, we plan to create an educational video that can be distributed and shown to minority cancer patients that will help them have a deeper understanding of the benefits of cancer clinical trials. This approach will be applicable across all cancers.
Neuroblastoma is the second most common tumor in childhood accounting for 7% of all children with cancer. There are about 800 new cases of neuroblastoma each year in the US. Treatments for neuroblastoma include surgery when tumors are localized or chemotherapy and radiation therapy when tumor spreads to other parts of the body. Cure rates are high for low-risk children, but only about 50% for high-risk children such as those whose tumor has spread. For these reasons, neuroblastoma is still the deadliest cancer in the childhood. With our research we aim at increasing the cure rates of neuroblastoma, particularly in high-risk children. To achieve this goal, we will harness the immune system of the children by instructing their lymphocytes to specifically identify a molecule called ALK in tumor cells. To obtain the highest potency and accuracy, we will exploit not only one immunotherapy, but rather a novel dual immunotherapy that will combine a cancer vaccine with engineered lymphocytes, both primed to recognize the same ALK target on tumor cells. This novel concept of dual immunotherapy will be tested in mouse models of neuroblastoma and will provide essential information on how the immune system can be exploited to target this tumor. These findings will lay the foundation for future clinical trials that will exploit this dual immunotherapy approach in children.
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