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，在治疗过程中只有有限的改善。 尽管付出了巨大的努力，但治疗效果。GBM表现出对化学治疗剂、辐射 和其他细胞死亡诱导物，在远离肿瘤原发灶的脑组织中定植， 固有的肿瘤内异质性，存在一个强大的肿瘤起始细胞（TIC）区室和多个 治疗的其他障碍。在开发有效的GBM治疗方面的另一个重大挑战是， 正常的CNS祖细胞和少突胶质细胞对大多数抗癌疗法比正常的CNS祖细胞和少突胶质细胞更脆弱。 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治疗的重要性， 转化细胞虽然一些新的疗法为一部分人提供了益处，但随着人们不断努力， 虽然我们不能更好地提前识别这些个体，但大多数GBM患者仍然没有得到有效的治疗。因此，在本发明中， 开发可以克服GBM细胞治疗抗性的多种机制的疗法 而不对CNS的正常细胞造成不可接受的毒性是本领域的核心需求。 本研究的中心假设是：（i）恢复激活c-Cbl泛素连接酶的能力 在GBM细胞中，特别是使用非经典氧化途径激活c-Cbl，能够靶向 具有单一治疗干预的GBM细胞的多种关键调节剂;（ii）恢复c-Cbl的药剂 可以通过基于机制的药物再利用来鉴定GBM细胞中的功能;（iii）c-Cbl恢复疗法 为合理的组合治疗提供了基础，这些组合治疗对GBM细胞的毒性比正常的GBM细胞更大。 神经胶质祖细胞;（iv）这种方法提供了临床相关的治疗方法， 在免疫缺陷NSG小鼠中颅内生长的人GBM;和（v）有可能前瞻性地 确定可能对本研究中开发的特定疗法有反应的GBM。初步数据来 支持这些假设中的每一个， 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： 假设候选CRA（迄今为止我们有10个）增加了对相关化合物的敏感性， 用于GBM治疗，能够同时靶向GBM中关键的多种蛋白质和生物活性 细胞功能和肿瘤生成，并实现这些结果，而不增加正常的敏感性， 神经胶质祖细胞与相关治疗剂。目的2检验基于CRA的治疗 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GBM。 目的3检验c-Cbl和Cool-1/c-pix之间的复合物的存在预测敏感性的假设 我们基于CRA的疗法，从而可能使前瞻性识别肿瘤最有可能是 响应这些方法。