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%的患者在诊断后2年内死亡。在本申请中，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，要么短暂，表明对化疗的新发或获得性耐药是导致不良结局的关键因素。此外，绝大多数患者局部复发，表明局部控制仍然难以捉摸，是实现治愈的关键步骤。为了建立在我们成功的努力，克服耐药性介导的AGT使用竞争性抑制剂O 6-BG，我们将集中在两个额外的重要介质的耐药性，包括DNA保护谷胱甘肽-S-转移酶（GSTP 1）和核DNA修复酶聚（ADP-核糖）聚合酶（PARP）。此外，我们鼓励 放射性标记的MAb如抗腱生蛋白MAb 81 C6或EGFR靶向毒素缀合物TP-38的结果证实了创新的肿瘤靶向治疗剂可以改善局部控制并改善总体结果。因此，我们还将评估靶向最近鉴定的肿瘤相关标志物的其他新疗法，所述肿瘤相关标志物例如EGFRvIII、糖蛋白NMB、多药耐药蛋白3、神经胶质瘤相关细胞表面神经节苷脂3 '-isoLM 1和3'，6 '-isoLD 1、人CMV和脊髓灰质炎病毒受体CD 155。我们的假设是，合理设计的新的治疗策略，无论是阻断化疗耐药的关键介质或增强局部控制，将提高患者的生存率， 恶性脑肿瘤，同时保持最佳的生活质量。该提案的具体目标是： 具体目标1。开展I期和II期临床试验，评估GST P1和PARP介导的化疗耐药抑制剂的抗肿瘤活性和安全性。具体目标2。进行I期和II期临床试验，以评估旨在改善局部控制的创新疗法的抗肿瘤活性和安全性，包括放射性标记的单克隆抗体、单克隆抗体片段、毒素缀合物、抗肿瘤相关CMV抗原的DC和溶瘤性脊髓灰质炎/鼻病毒重组体。具体目标3。确定这些治疗药物对恶性脑肿瘤患者总体生活质量的影响。

]'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.