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

基本信息

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
项目类别：
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

项目摘要

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) 是已知最致命的癌症之一，在治疗方面的改善有限尽管付出了大量努力，GBM仍表现出对化疗药物、放射线的耐药性。和其他细胞死亡诱导剂，在远离肿瘤原发源的脑组织中定植，并表现出固有的肿瘤内异质性，存在强大的肿瘤起始细胞（TIC）区室和多个开发有效的 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比正常的中枢神经系统祖细胞和少突胶质细胞更容易受到大多数抗癌疗法的影响。人们越来越认识到癌症治疗对癌细胞本身的不良神经副作用。重要问题，因此强调开发选择性毒性治疗方法的重要性虽然一些新疗法可以为一小部分人带来益处，但我们仍在不断努力为了更好地提前识别此类个体，大多数 GBM 患者仍然得不到有效的治疗。开发能够克服 GBM 细胞治疗耐药的多种机制的疗法因此，不对中枢神经系统正常细胞造成不可接受的毒性是该领域的核心需求。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，特别是使用非典型氧化途径来激活c-Cbl，能够靶向 (ii) 恢复 c-Cbl 的药剂 GBM 细胞的功能可以通过基于机制的药物再利用来识别 (iii) c-Cbl 恢复疗法；为合理的组合治疗奠定了基础，这些治疗对 GBM 细胞的毒性比对正常细胞的毒性更大 (iv) 这种方法提供了临床相关的疗法，可有效治疗既定的疾病人类 GBM 在免疫缺陷的 NSG 小鼠颅内生长；并且 (v) 有可能前瞻性地确定可能对本研究中开发的特定疗法产生反应的 GBM。提供了每个假设的支持，为了进一步发展这一有前景的研究途径，我们现在提出以下目标：目标 1 测试假设候选 CRA（目前为止我们有 10 个）会增加对相关化合物的敏感性 GBM 治疗中，能够同时靶向 GBM 中至关重要的多种蛋白质和生物活性细胞功能和肿瘤生成，并在不增加正常细胞敏感性的情况下实现这些结果目标 2 检验了基于 CRA 的疗法的假设。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 GBM。目标 3 检验 c-Cbl 和 Cool-1/ß-pix 之间复合物的存在可预测敏感性的假设到我们基于 CRA 的疗法，从而有可能能够前瞻性地识别最有可能发生的肿瘤对这些方法做出反应。