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.

Public Health Relevance

Glioblastome multiforme (GBM) is the most common and most detrimental form of brain tumor, with a current survival post diagnosis of as little at 14 months. The purpose of the current study is to investigate a novel therapeutic resistance gene we have found over expressed in GBM with the long term goal of identifying new therapeutic modalities to treat this devastating disease.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA187053-02
Application #
9122361
Study Section
Radiation Therapeutics and Biology Study Section (RTB)
Program Officer
Pelroy, Richard
Project Start
2015-08-07
Project End
2020-07-31
Budget Start
2016-08-01
Budget End
2017-07-31
Support Year
2
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Case Western Reserve University
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106