Polyamine Catabolism and Therapeutic Resistance in Glioblastoma Multiforme

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 DESCRIPTION (provided by applicant): Mediators of DNA damage, such as ionizing radiation, are frequently used for cancer therapy. Glioblastoma multiforme is the most common and severe form of brain tumor that is unfortunately resistant to most DNA damaging modalities, though they remain the standard of care. Here, in an attempt to define genetic determinants of therapeutic resistance in brain tumors, we have identified a novel mechanism of resistance to DNA damage that tumors employ that depends on the overexpression of a metabolic enzyme that we hypothesize is involved in regulating DNA and chromatin dynamics. The enzyme, spermidine/spermine-N1- acetyltrasferase 1 (SAT1), is a rate-limiting regulator of the catabolism of polyamines, ubiquitous positively charged small molecules that have been found to promote condensation of chromatin. By overexpressing SAT1, tumors are better prepared to repair deleterious double strand DNA breaks which require opening of chromatin to perform repair. In this application, we propose to 1) determine the mechanism of regulation of DNA repair by SAT1, 2) investigate the role of SAT1 as an epigenetic regulator of DNA repair related gene expression, and 3) determine the therapeutic benefit of inhibiting SAT1 expression in human tumors xenografted in mice. The overall goal is to determine if the polyamine pathway provides a novel target for therapeutic intervention in glioblastoma, while simultaneously revealing a previously unappreciated aspect of DNA repair regulation that depends on polyamine metabolism and chromatin remodeling.