THE DEVELOPMENT OF NOVEL THERAPEUTICS IN PANCREATIC AND BREAST CANCERS: POTENTIAL ROLE OF MUC1
1 online resource (221 pages) : PDF
University of North Carolina at Charlotte
Pancreatic ductal adenocarcinoma (PDA) is the 4th leading cause of cancer-related deaths in the US, and breast cancer (BC) contributes to ~40,000 deaths annually. The development of novel therapeutic agents for improving patient outcome is of paramount importance. Importantly, MUC1 is a mucin glycoprotein expressed on the apical surface of normal glandular epithelia but is over expressed and aberrantly glycosylated in >80% of human PDA and in >90% of BC. In the present study, we first utilize a model of PDA that is Muc1-null in order to elucidate the oncogenic role of MUC1. We show that lack of Muc1 significantly decreased proliferation, invasion, and mitotic rates both in vivo and in vitro. Next, we evaluated the anticancer efficacy of oncolytic virus (OV) therapy that utilizes viruses to kill tumor cells. The oncolytic potential of vesicular stomatitis virus (VSV) was analyzed in a panel of human PDA cell lines in vitro and in vivo in immune compromised mice. Our results demonstrate that VSV has potential as an OV against human PDA cells. Next, we tested oncolytic VSV in an immunocompetent mouse model. In agreement with our in vitro results, in vivo administration of live VSV resulted in the significant growth reduction of PDA tumors, with an enhanced efficacy when used in combination with a chemotherapeutic drug, gemcitabine. Finally, we tested a MUC1 specific tumor vaccine with targeted inhibition of immune suppression in a model of BC. Our results indicate that Indomethacin in combination with a MUC1 vaccine resulted in a significant reduction in tumor burden. These data, therefore, may have implications in the future design of MUC1-targeted therapies for BC and OV therapies for PDA.
Grdzelishvili, ValeryClemens, MarkDreau, DidierOgle, Craig
Thesis (Ph.D.)--University of North Carolina at Charlotte, 2013.
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