Abstracts Category : Other

Adenovirus Mediated Delivery of Decoy Hyper Binding Sitesfor Sequestration of an Oncogenic Transcription Factor HMGA as aPotential Novel Cancer Therapy and Antibacterial Activity of LocalMushrooms

by Faizule Hassan

The first section of this dissertation describes thedevelopment of strategies for the treatment of pancreatic cancerusing a novel synthetic DNA sequence that functions as decoybinding site for an oncogenic protein called high mobility group A(HMGA) and adenovirus mediated gene therapy. The second part ofthis dissertation describes a survey study for evaluating theantibacterial activity of mushroom samples collected from localareas. The Chapter 1 provides background information about the HMGAand its role in tumor development and cancer progression. TheChapter 1 also provides background information about the adenovirusand its use in cancer treatment. In addition, Chapter 1 discussesabout the medicinal use and antibacterial potential of mushrooms.In Chapter 2, we have devised a strategy of using engineeredreplication-defective adenovirus (Ad) to deliver decoy hyperbinding sites for HMGA to the nucleus of cancer cells with the goalof sequestering excess HMGA at the decoy hyper binding sites due tobinding competition. Sequestration of excess HMGA at the decoybinding sites is intended to reduce HMGA binding at the naturallyoccurring genomic HMGA binding sites, which should result innormalized gene expression and restored sensitivity tochemotherapy. Infection of five different pancreatic and livercancer cell lines with the Ad containing the HMGA decoy hyperbinding sites resulted in significant reduction in cell viabilityand increased sensitivity to chemotherapy. The Chapter 3 discussestoxicity and biodistribution following injection of the Adcontaining the HMGA decoy hyper binding sites into mice liver orpancreas. This study provides essential preclinical informationregarding toxicity and biodistribution needed to determine thepotential of our engineered virus for future treatment of cancer inhumans. The Cahpter 4 demonstrated a strategy to develop aconditionally replicating Ad virus which will selectively replicatein cancer cells while being unable to replicate in normal cells. Wehave shown that the deletion of two genes, E1ACR2 and E1B19K,increased cancer selective replication of the Ad and decreasechemotherapy resistance of pancreatic cacner cells. In Chapter 5,we have described a survey study where we showed antibacterialactivity in 25 mushroom samples out of the 75 samples tested.Finally the Chapter 6 summarizes the present research and showsfuture direction.Advisors/Committee Members: Kennedy, Michael (Advisor), Dabney-Smith, Carole (Committee Chair).