Polyamine Catabolism and Therapeutic Resistance in Glioblastoma Multiforme

 描述（由申请人提供）：DNA损伤介质，如电离辐射，经常用于癌症治疗。多形性胶质母细胞瘤是最常见和最严重的脑肿瘤形式，不幸的是，它对大多数DNA损伤方式具有抗性，尽管它们仍然是护理标准。在这里，在试图定义脑肿瘤中治疗抗性的遗传决定因素时，我们已经确定了肿瘤对DNA损伤的抗性的新机制，该机制依赖于我们假设参与调节DNA和染色质动力学的代谢酶的过表达。酶，亚精胺/精胺-N1-乙酰转移酶1（SAT 1），是多胺催化剂的限速调节剂，普遍存在的带正电荷的小分子，已被发现促进染色质的凝聚。通过过表达SAT 1，肿瘤更好地准备修复有害的双链DNA断裂，这需要打开染色质来进行修复。在本申请中，我们提出1）确定SAT 1调节DNA修复的机制，2）研究SAT 1作为DNA修复相关基因表达的表观遗传调节剂的作用，以及3）确定抑制SAT 1表达在小鼠异种移植的人肿瘤中的治疗益处。总体目标是确定多胺途径是否为胶质母细胞瘤的治疗干预提供了一个新的靶点，同时揭示了依赖于多胺代谢和染色质重塑的DNA修复调控的一个以前未被认识的方面。

 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.