Inhibition of the PI3 Kinase Pathway in Malignant Glioma by Convection Enhanced D

对流增强 D 抑制恶性胶质瘤中的 PI3 激酶途径

• 批准号: 7327951
• 负责人: JAMES S WALDRON
• 金额: $ 5.89万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7327951
• 关键词: 1-Phosphatidylinositol 3-Kinase; Adoptive Immunotherapy; Adoptive Transfer; Aftercare; Animals; Apoptosis; Binding; Biological; Biological Assay; CCI-779; Cell Line; Cell membrane; Cells; Characteristics; Chromosomes, Human, Pair 10; Chronic; Clinical; Clinical Trials; Combined Modality Therapy; Convection; Cytoplasm; Development; Dose; Drug Kinetics; Elevation; Evaluation; Event; Face; Glioma; Goals; High Pressure Liquid Chromatography; Histocytochemistry; Histologic; Homologous Gene; Human Development; Immune system; Immunosuppressive Agents; Immunotherapy; Implant; Infiltration; Intravenous; Kinetics; Link; Liposomes; Location; Malignant Glioma; Measures; Mediating; Medical; Membrane; Methods; Modality; Modeling; Molecular; Molecular Conformation; Nude Rats; Oncogenic; Oral; Outcome; PDPK1 gene; PTEN gene; Pathway interactions; Patients; Pharmaceutical Preparations; Phosphoinositide-3-Kinase, Catalytic, Gamma Polypeptide; Phosphoric Monoester Hydrolases; Phosphorylation; Population; Protein Kinase; Proteins; Proto-Oncogene Proteins c-akt; Public Health; Publishing; Research Project Grants; Resistance; Rodent; Rodent Model; Role; Route; Signal Transduction; Sirolimus; T-Lymphocyte; Testing; Therapeutic; Therapeutic Agents; Time; Toxic effect; Tumor Suppressor Genes; Vaccines; Variant; Work; Xenograft Model; Xenograft procedure; angiogenesis; brain tissue; clinical application; desire; extracellular; human FRAP1 protein; human PDCD1LG1 protein; implantation; improved; inhibitor/antagonist; innovation; killings; mTOR Inhibitor; neoplastic cell; nervous system disorder; phosphoinositide-3,4,5-triphosphate; response; tensin; therapy design; tripolyphosphate; tumor; tumor progression

DESCRIPTION (provided by applicant): Malignant glioma is a fatal neurological disease for which recent medical advances have only offered modest improvements in survival. PI(3)K pathway activation mediated by PTEN loss represents an important molecular feature of glioma progression. Multiple agents that target the PI(3)K pathway are under development. To date, these agents have been limited by systemic toxicity and demonstrated marginal efficacy. Convection enhanced delivery utilizing liposomal encapsulation represents a local delivery method with the potential to circumvent these limitations by delivering higher concentrations to the CNS while minimizing systemic toxicity. Hypothesis driven combination therapy with pathway specific inhibitors and other therapeutic modalities provides an avenue for the rational improvement of glioma therapy. Immunotherapy provides a tumor specific means of targeting glioma cells regardless of location in the CNS. Our recently published work has demonstrated a link between B7-H1 mediated tumor immunoresistance and PI(3)K pathway activation. The goal of our proposed study is to demonstrate that local delivery of PI(3)K inhibitors is more effective than systemic delivery and that a combined approach of PI(3)K inhibition and immunotherapy leads to improved therapeutic outcomes in the treatment of malignant glioma. Accordingly, we have developed the following specific aims: 1) To define the kinetics and magnitude of CNS and systemic toxicity of PI(3)K pathway inhibition 2) To analyze the molecular and therapeutic impact of PI(3)K pathway inhibition 3) To measure efficacy of combination therapy using adoptively transferred tumor specific T-cells after PI(3)K pathway inhibition. Our proposed project will evaluate the toxicity and efficacy of the mTOR inhibitor, CCI-779, after systemic delivery or local delivery by CED with and without liposomal encapsulation in a xenograft glioma rodent model. Combination therapy utilizing CED of inhibitor liposomes and the adoptive transfer of tumor specific CTLs into a rodent xenograft model will be assayed for therapeutic response. The proposed research project will directly contribute to public health by comparing response to systemic versus locally delivered inhibitors of a molecular pathway key to malignant glioma. The project will further explore the impact of inhibition of this pathway on resistance of glioma cells to attack by the immune system. Demonstration of improved outcomes with combination therapy will support the development of human clinical trials using specific pathway inhibition to improve response to immunotherapy.

描述（由申请人提供）：恶性神经胶质瘤是一种致命的神经系统疾病，最近的医疗进展仅提供了适度的生存改善。 PI（3）K途径激活由PTEN损失介导的激活代表了神经胶质瘤进展的重要分子特征。靶向PI（3）k途径的多种试剂正在开发中。迄今为止，这些药物受到全身毒性的限制，并表现出边缘疗效。利用脂质体封装的对流增强的交付代表了一种局部输送方法，有可能通过将较高的浓度向中枢神经系统传递到最小化系统性毒性，从而避免这些限制。假设驱动的联合疗法与途径特异性抑制剂和其他治疗方法为合理改善神经胶质瘤治疗提供了途径。免疫疗法提供了靶向神经胶质瘤细胞的特异性方法，而与中枢神经系统中的位置无关。我们最近发表的工作证明了B7-H1介导的肿瘤免疫力与PI（3）K途径激活之间的联系。我们提出的研究的目的是证明局部递送PI（3）K抑制剂比全身性递送更有效，并且PI（3）K抑制和免疫疗法的联合方法可改善恶性胶质瘤治疗的治疗结果。因此，我们已经开发了以下特定目的：1）定义CNS的动力学和大小PI的动力学和全身毒性（3）K途径抑制2），以分析PI（3）K途径抑制3的分子和治疗性影响分子和治疗性的影响，以测量使用tumor tumor tumor Temerted Temerted Temerted Temerted Temerted Temerted Temerted Temerted Temerted Temerted Temerted Temerted Temerted Temerted Temerted Temerted k in in Chand in in Chand in in Chand in in Chand in（3）。我们提出的项目将评估MTOR抑制剂CCI-779的毒性和功效，在系统性递送或通过有或没有脂质体封装的局部递送后，在异种移植膜片啮齿动物模型中。利用抑制剂脂质体CED以及将肿瘤特异性CTL转移到啮齿动物异种移植模型中的联合疗法将进行治疗反应。拟议的研究项目将直接通过比较对分子途径对恶性神经胶质瘤关键的系统性与局部传递抑制剂的反应进行比较。该项目将进一步探索抑制该途径对神经胶质瘤细胞对免疫系统攻击的耐药性的影响。结合疗法的改善结果的证明将支持使用特定途径抑制人类临床试验的发展，以改善对免疫疗法的反应。