Ap endo as a predictor of response to glioma therapy

描述(申请人提供)：胶质瘤是导致年轻人癌症死亡的第三大原因。世卫组织II级(低级别)和III级(间变性)胶质瘤构成了影响年轻人的大多数胶质肿瘤，发病高峰在35岁至45岁之间。中位生存期从2年到10年以上不等，但结果几乎都是致命的。放射治疗和以烷化剂为基础的化疗是主要的辅助治疗方法；然而，对于大多数II级和III级胶质瘤，疗效差异很大，并且没有预测标记物。为了提高现有辅助治疗的疗效，降低与治疗相关的发病率，识别适合于新疗法的胶质瘤并延长生存期，迫切需要确定可预测临床疗效的治疗特异性分子标志物。 这项应用解决了这样的假设，即无嘌呤核酸内切酶(AP Endo)活性是一种DNA修复活性，它处理细胞毒性基本部位，可以预测II级和III级胶质瘤对放射治疗和基于烷化剂的化疗的反应。根据基本的机制考虑和大量的支持数据，AP Endo活动是一个很好的预测标记物。重要的是，我们的新的先导性研究表明，无论是辅助放射治疗还是烷化剂治疗，AP Endo活性与肿瘤进展时间(TTP)之间存在强烈的负相关。为了解决我们的假设，我们将[1]分析在较大的II级和III级胶质瘤样本中放射治疗后AP Endo活性与TTP的相关性；[2]在较大的III级胶质瘤样本中分析AP Endo活性与TTP的相关性；以及[3]评估AP Endo的亚细胞定位，作为AP Endo活性的组织化学替代物。能够在现有的放射和烷化剂方案内更好地管理单个肿瘤，或者根据AP Endo的活性将肿瘤引导到替代或新的治疗方案，可以预期改善总体结果和生活质量。

DESCRIPTION (provided by applicant): Gliomas are the third leading cause of cancer deaths in young adults. WHO grade II (low-grade) and grade III (anaplastic) gliomas comprise the majority of glial tumors affecting younger adults, with peak incidence between 35 and 45 years of age. Median survival ranges from 2 to more than 10 years, but the outcome is nearly uniformly fatal. Radiotherapy and alkylating agent-based chemotherapy are the main adjuvant treatments; however, response is highly variable and there are no predictive markers for the majority of grade II and III gliomas. There is pressing need to identify treatment-specific molecular markers that are prognostic of clinical response, in order to improve the efficacy of existing adjuvant therapies, to reduce treatment associated morbidity, to identify gliomas that are candidates for novel therapies and to prolong survival. This application addresses the hypothesis that apurinic endonuclease (Ap endo) activity, a DNA repair activity that processes cytotoxic abasic sites, is predictive of response to radiotherapy and to alkylating agent-based chemotherapy in grade II and grade III gliomas. Ap endo activity is a prime candidate as a predictive marker, based on fundamental mechanistic considerations and substantial supporting data. Importantly, our new pilot study indicates that there is a strong, inverse correlation of Ap endo activity with time to tumor progression (TTP) following either adjuvant radiotherapy or alkylator therapy. To address our hypothesis, we will [1] analyze the association of Ap endo activity with TTP following radiotherapy in larger, separate samples of grade II and of grade III gliomas; [2] analyze the association of Ap endo activity with TTP following alkylating agent therapy in a larger sample of grade III gliomas; and [3] evaluate sub-cellular localization of Apel/Ref-1, the major human Ap endo, as a histochemical surrogate for Ap endo activity. The ability to better manage individual tumors within existing radiation and alkylating agent protocols, or to direct tumors to alternative or novel treatment regimens, based on Ap endo activity, can be expected to improve overall outcome as well as quality of life.