Polyamine Catabolism and Therapeutic Resistance in Glioblastoma Multiforme

Project: Research project

Description

? 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.
StatusActive
Effective start/end date8/7/157/31/20

Funding

  • National Institutes of Health: $351,131.00
  • National Institutes of Health: $342,596.00
  • National Institutes of Health: $361,136.00
  • National Institutes of Health: $362,569.00

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Spermine
Polyamines
Glioblastoma
DNA Repair
Chromatin
Brain Neoplasms
DNA Damage
Neoplasms
Therapeutics
Chromatin Assembly and Disassembly
Spermidine
Double-Stranded DNA Breaks
DNA
Enzymes
Standard of Care
Ionizing Radiation
Epigenomics
Gene Expression