DNA repair-based models of glioblastoma response to radiation and temozolomide

描述（由申请人提供）：胶质母细胞瘤是高度恶性的脑肿瘤，总是致命的。术后放疗（RT）同时给予甲基化剂替莫唑胺（TMZ）现在是新诊断的胶质母细胞瘤的公认标准治疗。然而，反应是高度异质性的，迫切需要治疗结果的标志物。我们的目标是开发基于DNA修复相关标志物的预测模型，该模型根据并行RT-TMZ后的进展风险对胶质母细胞瘤进行分层。DNA损伤是RT和烷化剂如TMZ的杀肿瘤活性的主要原因，DNA修复在确定临床反应中起主要作用。我们的预测模型将包括肿瘤Ap内切核酸酶（Ap endo）活性，其修复治疗诱导的脱碱基位点和DNA中的单链断裂。我们发表的和初步的工作表明，在不同的成人和儿童脑肿瘤中，包括50岁以下男性的初始样本中的胶质母细胞瘤，在RT或RT加烷化剂化疗后，Ap内分泌活性和治疗结果之间存在统计学显著的负相关性。我们的模型还将包括基因启动子的CpG甲基化状态、先前开发的标记或DNA修复蛋白O 6-甲基鸟嘌呤-DNA甲基转移酶（MGMT）的生化活性。在具体目标1中，我们将检验肿瘤Ap内分泌活性与接受同时RT-TMZ的成人胶质母细胞瘤的无进展生存期（PFS）呈负相关的假设。在具体目标2中，我们将检验以下假设：在多变量模型中纳入DNA修复和细胞死亡抗性的其他标志物将增强Ap内切酶活性的预测能力。在具体目标3中，我们将检验随机突变频率（最近已证明在人类肿瘤中升高）是PFS的预测标志物的假设。我们将使用考克斯回归分析，在包括MGMT启动子甲基化状态和其他潜在标志物的多变量模型中检查Ap endo活性与PFS之间的关联。公共卫生相关性：胶质母细胞瘤是一种致命的脑肿瘤，每年有10，000名美国成年人发病，平均生存期为9至15个月。手术后放疗和化疗的最新进展提高了大约一半患者的生存率，但剩下的一半患者没有受益，并且产生了很少或没有收益的副作用。我们的目标是通过开发预测对新疗法反应的肿瘤标志物来提高总生存率，以确定将受益的患者，并指导其他患者接受替代治疗，同时避免不必要的副作用。

DESCRIPTION (provided by applicant): Glioblastomas are highly malignant brain tumors that are invariably fatal. Post-operative radiotherapy (RT) given concurrently with the methylating agent temozolomide (TMZ) is now the accepted standard of care for newly diagnosed glioblastoma. Yet response is highly heterogeneous and there is urgent need for markers of treatment outcome. Our objective is to develop predictive models, based on DNA repair-related markers, which stratify glioblastomas by risk for progression following concurrent RT-TMZ. DNA damage is largely responsible for the tumoricidal activity of RT and alkylators such as TMZ, and DNA repair plays a major role in determining clinical response. Our predictive models will include tumor Ap endonuclease (Ap endo) activity, which repairs treatment-induced abasic sites and single- strand breaks in DNA. Our published and preliminary work has shown a statistically significant inverse association between Ap endo activity and treatment outcome following RT or RT plus alkylating agent based-chemotherapy in diverse adult and pediatric brain tumors, including glioblastomas in an initial sample of males under the age of 50. Our models will also include CpG methylation status of the gene promoter, a previously developed marker, or the biochemical activity, of the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT). In Specific Aim 1, we will test the hypothesis that tumor Ap endo activity is inversely associated with progression-free survival (PFS) in adult glioblastomas receiving concurrent RT-TMZ. In Specific Aim 2, we will test the hypothesis that inclusion of additional markers of DNA repair and resistance to cell death in multivariate models will strengthen the predictive power of Ap endo activity. In Specific Aim 3, we will test the hypothesis that random mutation frequency, which has recently been shown to be elevated in human tumors, is a predictive marker of PFS. We will use Cox regression analysis to examine the association between Ap endo activity and PFS in multivariate models that include MGMT promoter methylation status and additional potential markers. PUBLIC HEALTH RELEVANCE: Glioblastomas are fatal brain tumors that strike 10,000 American adults each year, the average survival being between 9 and 15 months. A recent advance in post-surgical radiation and chemotherapy has improved survival for about half of patients, but the remaining half do not benefit and incur side effects for little or no gain. Our goal is to increase overall survival by developing tumor markers that predict response to the new therapy, in order to identify patients who will benefit and to direct others to alternative treatments while sparing them unnecessary side effects.