CORE-3-PHASE I/II CLINICAL TRIALS

原发性恶性脑肿瘤患者的预后仍然令人沮丧，超过90%的患者在确诊后两年内死亡。在本应用程序中，我们将重点关注成功治疗这些肿瘤患者的两个主要障碍。对化疗的反应要么不存在，要么是短暂的，这表明对化疗的新生或获得性耐药是不良预后的关键因素。此外，绝大多数患者局部复发，表明局部控制仍然难以捉摸，这是实现治愈的关键一步。在我们利用竞争性抑制剂O6-BG成功克服AGT介导的化学耐药的基础上，我们将重点研究另外两种重要的化学耐药介质，包括DNA保护剂谷胱甘肽- s -转移酶（GSTP1）和核DNA修复酶聚（adp -核糖）聚合酶（PARP）。此外，我们的鼓励

]'he outcome for patients with primary malignant brain tumors remains dismal with over 90% of patients dying within 2 years of diagnosis. In this application we will focus on two major roadblocks to successful treatment for patients with these tumors. Response to chemotherapy is either non-existent or short-lived indicating that de novo or acquired resistance to chemotherapy is a critical contributor to poor outcome. In addition, the vast majority of patients recur locally indicating that local control remains elusive and represents a critical step to achieve a cure. To build upon our successful efforts to overcome chemoresistance mediated by AGT using the competitive inhibitor O6-BG, we will focus on two additional important mediators of chemoresistance including the DNA protectant glutathione-S-transferase (GSTP1) and the nuclear DNA repair enzyme poly(ADP-ribose) polymerase (PARP). In addition, our encouraging results with radiolabeled MAbs such as the anti-tenascin MAb 81 C6 or the EGFR-targeting toxin-conjugate TP-38, confirm that innovative tumor-targeting therapeutics can improve local control and improve overall outcome. We therefore will also evaluate additional novel therapeutics targeting recently identified tumor-associated markers such as EGFRvIII, glycoprotein NMB, multidrug resistant protein 3, the gliomaassociated cell-surface gangliosides 3'-isoLM1 and 3',6'-isoLD 1, human CMV and the poliovirus receptor CD155. Our HYPOTHESIS is that rationally designed, novel therapeutic strategies that either block key mediators of chemoresistance or that augment local control, will improve the survival of patients with malignant brain tumors while preserving an optimal quality of life. The Specific Aims of this proposal are: Specific Aim 1. To conduct Phase I and II clinical trials to assess the anti-tumor activity and safety of inhibitors of chemoresistance mediated by GSTP1 and PARP. Specific Aim 2. To conduct Phase I and II clinical trials to assess the anti-tumor activity and safety of innovative therapeutics designed to improve local control including radiolabeled MAbs, MAb fragments, toxin conjugates, DCs against tumor-associated CMV antigens and an oncolytie polio/rhinovirus recombinant. Specific Aim 3. To determine the impact of these therapeutic agents on overall quality of life for patients with malignant brain tumors.