CORE-3-PHASE I/II CLINICAL TRIALS

原发恶性脑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。在这项应用中，我们将重点关注成功治疗这些肿瘤患者的两个主要障碍。对化疗的反应要么是不存在的，要么是短暂的，这表明从头开始的或获得性的化疗耐药是导致不良预后的关键因素。此外，绝大多数患者局部复发表明，局部控制仍然难以实现，这是实现治愈的关键一步。为了利用竞争性抑制剂O6-BG克服AGT介导的化疗耐药，我们将重点研究另外两个重要的化疗耐药介质，包括DNA保护剂谷胱甘肽-S转移酶(GSTP1)和核DNA修复酶多聚(ADP-核糖)聚合酶(PARP)。此外，我们令人鼓舞的是 结果用放射性标记的单抗，如抗Tenascin单抗81C6或EGFR靶向毒素结合物TP-38，证实了创新的肿瘤靶向治疗方法可以改善局部控制和改善整体结果。因此，我们还将评估针对最近发现的肿瘤相关标记物的其他新疗法，如EGFRvIII、糖蛋白NMB、多药耐药蛋白3、胶质瘤相关细胞表面神经节苷脂3‘-isLM1和3’，6‘-iSold 1、人巨细胞病毒和脊髓灰质炎病毒受体CD155。我们的假设是，合理设计、新颖的治疗策略，无论是阻断化疗耐药的关键媒介，还是增强局部控制，都将提高卵巢癌患者的存活率。 在保持最佳生活质量的同时，治疗恶性脑瘤。这项建议的具体目标是： 具体目的1.进行I期和II期临床试验，评价GSTP1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.进行第一阶段和第二阶段临床试验，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抗、单抗片段、毒素结合物、抗肿瘤相关巨细胞病毒抗原的树突状细胞和重组脊髓灰质炎/鼻病毒。具体目的3.确定这些治疗药物对恶性脑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.