Lung cancer accounts for the largest number of cancer deaths for both men and women. While there have been recent advances in treatment options for patients having lung tumors that have specific mutations, or by harnessing patients own immune systems, the vast majority of patients with advanced tumors will not respond to these treatments or they will relapse following an initial response. A common feature of lung tumors is their increased production of antioxidants, which promote their growth and survival and which contribute to resistance to therapies. The DeNicola lab studies how the production of antioxidants by lung tumor cells affects these processes, and how blocking antioxidant production inhibits tumor formation and progression.
We recently found that many lung tumors increase their levels of an antioxidant protein called NNT, which was not previously associated with lung cancer. Notably, studies of the DeNicola lab show that if NNT is not present, lung tumors cannot form. In these V Foundation Scholar studies, we will define how NNT is regulated in lung cancer cells, and will develop strategies to block the function of NNT. In addition, we seek to understand how NNT promotes tumor formation. These studies will provide an improved understanding of NNT, and will allow us to design better therapies for lung cancers that have increased NNT levels.
Funded by the Stuart Scott Memorial Cancer Research Fund
American men of African descent (AAM) are known to experience greater incidence of and mortality from prostate cancer (PCa) than their Caucasian (EAM) counterparts. The determinants of this high rate of PCa in men of African descent remain unresolved. The genomic and epigenomic contribution to PCa disparity has been well established with the identification of significant racial differences in DNA methylation level and expression of various genes. In the last decade a number of biomarker-driven predictive tools have been developed for clinical use to aid in PCa treatment decisions. These biomarkers show promise as predictors of aggressive and lethal PCa with potential clinical utility. However, these predictive tools were developed mostly from EAM specimens. There is a lack of data on the relevance of these biomarkers on observed increased aggressiveness and lethal PCa among AAM. We and others have provided evidence suggesting that AAM with aggressive phenotypes have significantly different methylation level and expression of many PCa biomarkers compared to EAM, suggesting that these may be ideal prognostic biomarkers for AAM. Therefore, comparative evaluation of biomarkers for aggressive PCa in AAM is imperative, and carries the inherent potential to elucidate the pathogenesis of aggressive and lethal PCa in this at-risk population. The focus of this proposal is to unravel the epigenetic and genomic predictors of aggressive and lethal PCa in AAM. The implications of our proposed study have immense clinical relevance in this era of personalized medicine for the at-risk population of AAM.
Brain cancer is now the leading cause of cancer‐related death in children, due to the significant improvements in outcomes for children with more common cancers such as leukemia. This research proposal advances a novel immunotherapy treatment for medulloblastoma (MB), the most common malignant brain tumor in children. We have pioneered a treatment platform for pediatric brain tumors called adoptive cellular immunotherapy, which involves expanding tumor‐reactive ‘killer T cells’ to large numbers outside of a patient and delivering these potent immune cells back to children with resistant brain tumors. This approach is currently undergoing evaluation in first‐in‐human clinical trials at our center. This project will advance this platform into a next generation approach that uses genomic technology to identify patient‐specific antigens expressed in medulloblastoma tumors and specifically isolate and expand T cells recognizing these unique tumor targets (called neoantigens). If the objectives of this study are met, we will be able to significantly enhance the specificity and potency of an already promising platform and rapidly translate our findings into innovative clinical trials for children battling brain cancer.
Neuroblastoma is an aggressive cancer of the nervous system that primarily affects very young children. Half of the children affected by this disease are less than 18 months old. Neuroblastoma represents 8-10% of all childhood cancer cases, but 15% of all childhood cancer deaths, and over the past twenty years, the survival statistics have not improved, with only 40% of all affected children expected to have any hope of a long-term survival. Treatments for neuroblastoma are generally aggressive, and include multiple treatment types including surgery, radiation, chemotherapy, and hematopoietic progenitor cell (HPC) transplant (more often referred to as bone marrow transplant). It is this latter treatment type, HPC transplant, that was associated with the greatest improvement in survival when it was introduced for neuroblastoma treatment over 20 years ago, and which forms the foundation for this proposal. In treating neuroblastoma, the actual transplant is preceded by a regimen of very high dose chemo- and radiation-therapy. This reduces the patient’s tumor burden to the lowest possible level, but also wipes out the blood forming cells of the bone marrow. The HPC that are transplanted re-establish healthy bone marrow. In the process of marrow re-establishment, the patient’s immune system also re-establishes. It has been seen in animal models and in some clinical situations that a specific type of cells in the immune system, called lymphocytes, will preferentially recognize and respond to the agents in vaccines if those vaccines are administered early during this re-establishment process. Our goal in the proposed study will be to create vaccines from killed neuroblastoma cells taken from each patient, and then to administer those vaccines during recovery from HPC transplant. We will follow all patients in this study for an entire year to determine if this vaccine protocol produces immunity against the patient’s own neuroblastoma cells, and also if it results in tumor suppression. Autologous HPC transplant has been used in the treatment of neuroblastoma for over twenty years, but the success of this therapy has remained below 40 percent. Dendritic cell therapy has been tested in a very limited number of patients with some hint of promise. This study will be the first effort to combine these two approaches in a way that we expect to be synergistic. This unique study is being carried out as a collaborative effort between the Cell Therapies Facility of the MoffittCancerCenter and the Blood and Marrow Transplant Unit of All Children’s Hospital.
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