Identifier

etd-10252010-144927

Degree

Doctor of Philosophy (PhD)

Department

Biomedical and Veterinary Medical Sciences - Comparative Biomedical Sciences

Document Type

Dissertation

Abstract

Advances in cancer therapies continue to be improved, yet cancer continues to be one of the deadliest diseases in the world. Harnessing the power of the body’s immune system to attack cancer is a promising strategy that can further improve therapies for neoplastic diseases. As part of this strategy, cytokines such as interleukin (IL) 2 and interferon á are currently accepted cancer treatments, and other cytokines such as IL12 and GM-CSF also show potential as new treatments. Clinical trials with these cytokines have shown less than acceptable therapeutic efficacy and toxicities, but tumor-targeting motifs can improve these effects. Both antibodies and peptides specific for tumor antigens have been used in recombinant protein and gene therapy systems to increase the intratumoral cytokine accumulation and decrease systemic toxicities. Still, these treatments have not been capable of overcoming the obstacles for clinical acceptance. The hypothesis tested in this dissertation is that inserting tumor-targeting peptide coding sequences into IL12 plasmid DNA will create a novel systemic gene therapy approach which will increase the antitumor efficacy and decrease toxicity for cancer treatments. To accomplish this goal, a reporter gene mediated screening strategy was developed to identify a peptide which can target multiple tumor models. While preparing this method, it was discovered that these peptides can have a strong effect on the activity of the conjugated reporter gene. Once this strategy was finalized, the peptide VNTANST was found to increase the intratumoral accumulation of the reporter gene in five tumor models including a human xenogeneic model. The VNTANST coding sequence was then inserted into an IL12 plasmid to examine the antitumor efficacy. In breast adenocarcinoma, squamous cell carcinoma, and colon carcinoma models, VNTANST-IL12 plasmid DNA treatments distal from the tumor site increased tumor inhibition and, in two models, prolonged survival. Also, these treatments reduced the development of metastatic lung tumors in a spontaneous metastatic model. As expected, these tumor-targeted IL12 treatments decreased the level of liver toxicity compared to wild-type treatments. The receptor for VNTANST was identified as vimentin, which is a potentially powerful target for human cancers.

Date

2010

Document Availability at the Time of Submission

Release the entire work immediately for access worldwide.

Committee Chair

Barker, Steven A

DOI

10.31390/gradschool_dissertations.1601

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