Novel Strategies for Brain Tumor Therapy

脑肿瘤治疗新策略

• 批准号: 8265856
• 负责人: Ian F. Pollack
• 金额: $ 123.74万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8265856
• 关键词: Accounting; Address; Adult; Antigen-Presenting Cells; Antigens; Apoptosis; Area; Basic Science; Biological; Biological Products; Biometry; Brain Neoplasms; CXCL10 gene; Cell Line; Cell Maturation; Cell physiology; Cells; Child; Childhood Brain Neoplasm; Clinical; Clinical Protocols; Clinical Research; Clinical Trials; Collaborations; Dendritic Cells; Development; Effector Cell; Engineering; Epitopes; Evaluation; Fostering; Foundations; Gene Delivery; Genotype; Glioma; Goals; Herpesviridae; Image; Immunization; Immunologic Monitoring; Individual; Institution; Interferon-alpha; Laboratories; Maintenance; Malignant Glioma; Malignant neoplasm of brain; Mediating; Microscopic; Modeling; Monitor; Neuraxis; Normal tissue morphology; Oncolytic; Operative Surgical Procedures; Patients; Peptides; Phenotype; Poly ICLC; Pre-Clinical Model; Primary Brain Neoplasms; Program Research Project Grants; Protocols documentation; Radiation therapy; Research Activity; Research Infrastructure; Research Personnel; Resources; Sampling; Series; Serum; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Systemic Therapy; Techniques; Therapeutic; Tissue Banking; Tissue Banks; Tissues; Tumor Tissue; Vaccination; Virus; Virus Replication; base; biological preparation; cell killing; cellular transduction; conventional therapy; imaging modality; immunoreactivity; improved; innovation; killings; multidisciplinary; neoplastic cell; novel; novel strategies; novel therapeutics; outcome forecast; pre-clinical; preclinical study; programs; statistics; therapy design; transduction efficiency; treatment strategy; tumor; tumor growth; vector

DESCRIPTION (provided by applicant): The prognosis for patients with malignant brain tumors has improved minimally in the last two decades; median survival is less than one year for patients with malignant glioma, the most common primary brain tumor. These statistics provide a strong rationale for coordinated efforts to identify innovative approaches to treat these tumors. The unifying hypothesis of this program project is that novel therapeutic strategies that take into account the unique features of these tumors will induce tumor regression, and potentiate conventional therapies. Each project is translationally oriented, with a common goal of addressing fundamental biological issues relevant to tumor growth and evaluating innovative treatment approaches using a series of preclinical models, as a basis to identify promising strategies to advance into clinical therapies. Project 1 is based on the hypothesis that inhibition of aberrantly activated signal transduction pathways, or activation of apoptosis signaling, will induce glioma cell killing, potentially in a genotype-specific fashion, and that this approach will have independent activity in glioma models, and potentiate other approaches. Project 2 postulates that vaccination with glioma-associated antigen epitopes, in conjunction with systemic therapy designed to enhance immunoreactivity in the brain tumor microenvironment, will be an effective mechanism for antigen delivery to antigen-presenting cells, and that the conditions for immunization can be optimized using signaling or vector-mediated strategies that promote dendritic cell maturation and function, in collaboration with Projects 1 and 3. Project 3 postulates that gene delivery to the brain tumor microenvironment, using oncolytic Herpes virus vectors incorporating novel multigene constructs engineered to facilitate virus incorporation, spread, and transduction efficiency, can achieve tumor killing and enhance the effects of other treatment strategies. This project will also generate many of the vector constructs that will be used in Projects 1 and 2. The Administrative/Biostatistics/Clinical Support Core (A) provides essential infrastructure support for the activities of this program. The Cellular and Tissue Imaging Core (B) provides a panoply of advanced microscopic imaging capabilities used in each of the projects. The Immunological Monitoring and Cellular Products Laboratory Core (C) provides banking of tissue and serum samples, maintenance of cell lines, preparation of biological products, and therapeutic monitoring essential for the clinical protocols in this program. Relevance: Taken together, the multidisciplinary interactions that have evolved in this program optimize our chances to identify and refine promising approaches that can be applied clinically to improve the prognosis of patients with malignant gliomas.

描述（由申请人提供）： 过去二十年来，恶性脑肿瘤患者的预后改善甚微；恶性胶质瘤（最常见的原发性脑肿瘤）患者的中位生存期不到一年。这些统计数据为协调努力确定治疗这些肿瘤的创新方法提供了强有力的理由。该计划项目的统一假设是，考虑到这些肿瘤独特特征的新治疗策略将诱导肿瘤消退，并增强传统疗法。每个项目都是以转化为导向的，其共同目标是解决与肿瘤生长相关的基本生物学问题，并使用一系列临床前模型评估创新治疗方法，作为确定有希望进入临床治疗的策略的基础。项目 1 基于这样的假设：抑制异常激活的信号转导途径或激活细胞凋亡信号，将可能以基因型特异性的方式诱导神经胶质瘤细胞死亡，并且该方法将在神经胶质瘤模型中具有独立的活性，并增强其他方法。项目 2 假设，用神经胶质瘤相关抗原表位进行疫苗接种，结合旨在增强脑肿瘤微环境中免疫反应性的全身治疗，将成为将抗原递送至抗原呈递细胞的有效机制，并且可以使用促进树突状细胞成熟和功能的信号传导或载体介导的策略来优化免疫条件，与 项目 1 和 3。项目 3 假设使用溶瘤疱疹病毒载体将基因递送到脑肿瘤微环境，该载体结合了旨在促进病毒掺入、传播和转导效率的新型多基因构建体，可以实现肿瘤杀伤并增强其他治疗策略的效果。该项目还将生成许多将在项目 1 和 2 中使用的载体构建体。行政/生物统计/临床支持核心 (A) 为本计划的活动提供必要的基础设施支持。细胞和组织成像核心 (B) 提供了每个项目中使用的一整套先进的显微成像功能。免疫监测和细胞产品实验室核心 (C) 提供组织和血清样本库、细胞系维护、生物产品制备以及该计划中临床方案所必需的治疗监测。相关性：总而言之，该计划中发展的多学科互动优化了我们识别和完善可在临床上应用的有前途的方法的机会，以改善恶性胶质瘤患者的预后。

项目成果

LOH in the HLA class I region at 6p21 is associated with shorter survival in newly diagnosed adult glioblastoma.

• DOI: 10.1158/1078-0432.ccr-12-2861
• 发表时间: 2013-04-01
• 期刊: Clinical cancer research : an official journal of the American Association for Cancer Research
• 作者: Yeung JT;Hamilton RL;Ohnishi K;Ikeura M;Potter DM;Nikiforova MN;Ferrone S;Jakacki RI;Pollack IF;Okada H
• 通讯作者: Okada H

Expression of antigen processing and presenting molecules in brain metastasis of breast cancer.

• DOI: 10.1007/s00262-011-1137-9
• 发表时间: 2012-06
• 期刊: CANCER IMMUNOLOGY IMMUNOTHERAPY
• 影响因子: 5.8
• 作者: Liu, Yan;Komohara, Yoshihiro;Domenick, Natalie;Ohno, Masasuke;Ikeura, Maki;Hamilton, Ronald L.;Horbinski, Craig;Wang, Xinhui;Ferrone, Soldano;Okada, Hideho
• 通讯作者: Okada, Hideho

MicroRNAs in immune regulation--opportunities for cancer immunotherapy.

• DOI: 10.1016/j.biocel.2010.02.002
• 发表时间: 2010-08
• 期刊: INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY
• 影响因子: 4
• 作者: Okada, Hideho;Kohanbash, Gary;Lotze, Michael T.
• 通讯作者: Lotze, Michael T.

Survivin inhibitor YM155 induces mitochondrial dysfunction, autophagy, DNA damage and apoptosis in Bcl-xL silenced glioma cell lines.

• DOI: 10.1002/mc.22587
• 发表时间: 2017-04
• 期刊: Molecular carcinogenesis
• 影响因子: 4.6
• 作者: Jane EP;Premkumar DR;Sutera PA;Cavaleri JM;Pollack IF
• 通讯作者: Pollack IF

YM-155 potentiates the effect of ABT-737 in malignant human glioma cells via survivin and Mcl-1 downregulation in an EGFR-dependent context.

• DOI: 10.1158/1535-7163.mct-12-0901
• 发表时间: 2013-03
• 期刊: Molecular cancer therapeutics
• 影响因子: 5.7
• 作者: Jane EP;Premkumar DR;DiDomenico JD;Hu B;Cheng SY;Pollack IF
• 通讯作者: Pollack IF