Date of Award

5-6-2009

Document Type

Thesis

Degree Name

Medical Doctor (MD)

First Advisor

Joseph Peipmeier

Abstract

Glioblastoma multiforme is one the most dreaded diagnoses in medicine. They comprise almost 80% of all primary malignant intracranial neoplasms, carry a 5-year survival rate of 3-5%, and the outcome of the disease has not improved in the past 3 decades. At the forefront of the array of treatment options being explored to change this prognosis are conditionally replicative oncolytic adenoviruses (CRAd), adenoviruses targeted to selectively replicate only in cancer cells. Here we present the results of the characterization of the ICOVIR-5 adenovirus, which contains an RGD peptide motif inserted into the viral fiber knob for increased transduction, a deletion in the viral early 1A gene (E1A), and an E2F promoter driving expression of the modified E1A gene, taking advantage of the over expression of E2F in glioma cells. We demonstrated that in glioma cells, ICOVIR-5's E2F promoter was occupied by free E2F, thus driving both E1A expression and viral replication. This was not the case in normal human astrocytes (NHA), where there was no noticeable viral replication. Restoration of the retinoblastoma pathway in glioma cells abrogated ICOVIR-5's replication, demonstrating that the virus would not replicated in normal cells or rescued cancer cells. Also, a potent antiglioma effect was shown both in vivo and in vitro. Xenografted mice receiving intratumoral ICOVIR-5 injection had a significantly increased median survival (P < 0.0001), and almost 40% of the treated mice survived long term disease free. The high selectivity and antiglioma potency of the ICOVIR-5 virus warrants further evaluation in clinical trials.

Comments

This thesis is restricted to Yale network users only. This thesis is permanently embargoed from public release.

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