Mechanism-based drug repurposing and novel treatments for glioblastoma

基于机制的药物再利用和胶质母细胞瘤的新疗法

• 批准号: 9453659
• 负责人: MARK D NOBLE
• 金额: $ 35.23万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-15 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9453659
• 关键词: 1-Phosphatidylinositol 3-Kinase; 1-Phosphatidylinositol 4-Kinase; Abbreviations; Adverse effects; Antineoplastic Agents; Biological; Biological Process; CASP8 and FADD-like apoptosis regulating protein; Cell Compartmentation; Cell Death; Cell division; Cell physiology; Cells; Cephalic; Clinical; Combined Modality Therapy; Complex; Data; Development; ERBB2 gene; Ephrins; Epidermal Growth Factor Receptor; Estrogen Receptor alpha; Exhibits; FGFR2 gene; FOXM1 gene; FRAP1 gene; Fibroblast Growth Factor Receptor 2; Foundations; Generations; Genes; Genetic Transcription; Glioblastoma; Goals; Heat-Shock Proteins 70; Human; IL6ST gene; Immune; Immunodeficient Mouse; Individual; Insulin-Like-Growth Factor I Receptor; Integrin alpha5; Intervention; Investigation; Italy; Laboratories; MET gene; MGMT gene; Malignant Neoplasms; Malignant neoplasm of brain; Mediating; Movement; Mus; NF-kappa B; Neurologic; Normal Cell; O-(6)-methylguanine; Oligodendroglia; Outcome; Oxidation-Reduction; Oxides; PIX protein; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Phosphotransferases; Platelet-Derived Growth Factor alpha Receptor; Primary Neoplasm; Proteins; Receptor Protein-Tyrosine Kinases; Regulation; Research; Resistance; Role; STAT3 gene; Serum Response Element; Signal Transduction; Stat3 protein; Stat5 protein; Stem cells; Tamoxifen; Testing; Therapeutic Agents; Therapeutic Intervention; Toxic effect; Treatment outcome; Tumor Initiators; base; beta catenin; brain cell; brain tissue; cancer cell; cancer therapy; cell motility; cell transformation; chemotherapeutic agent; clinically relevant; combinatorial; effective therapy; glycoprotein 130; heat-shock factor 1; interest; irradiation; notch protein; novel; novel therapeutics; oxidation; progenitor; programs; prospective; protein activation; protein function; receptor; restoration; sex; temozolomide; therapy development; therapy resistant; tumor; tumor growth; tumor heterogeneity; tumor initiation; ubiquitin ligase

Glioblastomas (GBMs) are among the most deadly cancers known, with only limited improvements in treatment outcomes despite extensive efforts. GBMs exhibit resistance to chemotherapeutic agents, irradiation and other cell death inducers, colonize brain tissue far removed from the tumor's primary origin, and exhibit intrinsic intra-tumor heterogeneity, the presence of a robust tumor initiating cell (TIC) compartment and multiple other obstacles to treatment. Still a further significant challenge in developing effective GBM treatments is that normal CNS progenitor cells and oligodendrocytes are more vulnerable to most anticancer therapies than are cancer cells themselves. Adverse neurological side effects of cancer treatment are increasingly recognized as important problems, thus emphasizing the importance of developing treatments that are selectively toxic for transformed cells. While some new therapies offer benefit to a subset of individuals, with ongoing efforts to better identify such individuals in advance, most GBM patients remain without effective treatment. Thus, development of therapies that can overcome the multiple mechanisms of therapeutic resistance of GBM cells without causing unacceptable toxicity to normal cells of the CNS is thus a central need in this field. The central hypotheses of this research are that (i) restoring the ability to activate the c-Cbl ubiquitin ligase in GBM cells, and in particular using a non-canonical oxidation pathway to activate c-Cbl, enables targeting of multiple critical regulators of GBM cells with a single therapeutic intervention; (ii) agents that restore c-Cbl function in GBM cells can be identified by mechanism-based drug repurposing; (iii) c-Cbl restoration therapies provide a foundation for rational combinatorial treatments that are more toxic for GBM cells than for normal glial progenitors; (iv) this approach provides clinically relevant therapies that re effective in treating established human GBMs growing intra-cranially in immune-deficient NSG mice; and (v) it is possible to prospectively identify GBMs that are likely to respond to specific therapies developed in this research. Preliminary data to support each of these hypotheses is provided, To further develop this promising avenue of investigation, we now propose the following aims: Aim 1 tests the hypothesis that candidate CRAs (of which we thus far have ten) increase sensitivity to compounds relevant to GBM treatment, enable simultaneous targeting of multiple proteins and biological activities critical in GBM cell function and tumor generation and achieves these outcomes without increasing the sensitivity of normal glial progenitor cells to relevant therapeutic agents. Aim 2 tests the hypothesis that CRA-based therapies enable effective treatment of human GBMs, growing in immunodeficient mice, in a clinically relevant manner. Aim 3 tests the hypothesis that the presence of complexes between c-Cbl and Cool-1/ß-pix predicts sensitivity to our CRA-based therapies, thus potentially enabling prospective identification of tumors most likely to be responsive to these approaches.

胶质母细胞瘤(GBM)是已知的最致命的癌症之一，在 尽管作出了广泛的努力，但还是取得了治疗结果。GBM对化疗药物、辐射具有抵抗力 和其他细胞死亡诱导剂，定植远离肿瘤主要来源的脑组织，并展示 固有的肿瘤内异质性，存在一个强大的肿瘤起始细胞(TIC)隔室和多个 治疗的其他障碍。开发有效的GBM治疗方法的另一个重大挑战是 正常的中枢神经系统祖细胞和少突胶质细胞对大多数抗癌治疗比 癌细胞本身。癌症治疗的不良神经副作用越来越被认为是 重要的问题，从而强调了开发选择性毒性的治疗方法的重要性 转化的细胞。虽然一些新的疗法为一部分人提供了好处，但随着不断努力 为了更好地提前识别这些患者，大多数GBM患者仍然没有得到有效的治疗。因此， 克服GBM细胞治疗耐药的多种机制的研究进展 因此，在不对中枢神经系统正常细胞造成不可接受的毒性的情况下，这是该领域的核心需求。 这项研究的中心假设是：(I)恢复激活c-Cbl泛素连接酶的能力 在GBM细胞中，特别是使用非规范氧化途径激活c-Cbl，使靶向 通过单一治疗干预对GBM细胞进行多个关键调节；(Ii)恢复c-Cbl的药物 GBM细胞的功能可以通过基于机制的药物再利用来确定；(Iii)c-Cbl修复疗法 为合理的联合治疗提供了基础，这种联合治疗对GBM细胞的毒性比正常细胞更大 神经胶质前体细胞；(Iv)这种方法提供了临床上相关的治疗方法，在治疗已确定的 人的GBM在免疫缺陷的NSG小鼠体内生长；以及(V)有可能在未来 确定可能对本研究中开发的特定疗法有反应的基底膜。初步数据将 提供了对这些假设中的每一个的支持， 为了进一步发展这一有希望的研究途径，我们现在提出以下目标：Aim 1测试 假设候选CRA(到目前为止我们有10个)增加了对相关化合物的敏感性 对于GBM治疗，允许同时靶向在GBM中至关重要的多个蛋白质和生物活性 细胞功能和肿瘤生成，并在不增加正常的敏感性的情况下实现这些结果 神经胶质前体细胞与相关治疗药物的关系。Aim 2验证了基于CRA的治疗方法的假设 能够以临床相关的方式有效治疗在免疫缺陷小鼠中生长的人类基底膜。 Aim 3验证了c-Cbl和Cool-1/？-pix之间的复合体的存在预测敏感性的假设 到我们基于CRA的治疗，从而潜在地使前瞻性识别最有可能是 对这些方法作出回应。