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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：
9891963
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/9891963
关键词：
1-Phosphatidylinositol 3-Kinase 1-Phosphatidylinositol 4-Kinase Abbreviations 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 ITGA5 gene Immune Immunodeficient Mouse Individual Insulin-Like-Growth Factor I Receptor 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 Tamoxifen Testing Therapeutic Agents Therapeutic Intervention Toxic effect Treatment outcome 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 side effect stem cells 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（GBMs）是已知的最致命的癌症之一，在治疗方面的进展有限