Targeting physical stress-driven mechanisms to overcome glioblastoma treatment resistance

针对物理压力驱动机制克服胶质母细胞瘤治疗耐药性

• 批准号: 10273309
• 负责人: Rakesh K. Jain
• 金额: $ 62.38万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-22 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10273309
• 关键词: Affect; Animal Model; Animals; Antibodies; Antigen-Presenting Cells; Biological Assay; Biomedical Engineering; Biotechnology; Blood Vessels; Brain Neoplasms; C57BL/6 Mouse; Cell Nucleus; Cell Proliferation; Cell Survival; Cells; Cephalic; Clustered Regularly Interspaced Short Palindromic Repeats; Combined Modality Therapy; Confined Spaces; Cytoplasm; Data; Data Set; Diagnosis; Environment; Epithelial; Exposure to; Genes; Genetic; Genetic Transcription; Glioblastoma; Goals; Growth; Human; Hypoxia; ITIM; Immune; Immune response; Immune system; Immunity; Immuno-Chemotherapy; Immunocompetent; Immunoglobulin G; Immunoprecipitation; Immunosuppression; Immunotherapy; Implant; In Vitro; Kinetics; Malignant Neoplasms; Malignant neoplasm of brain; Measures; Mechanical Stress; Mechanics; Mediating; Mesenchymal; Messenger RNA; Methods; Mus; Nature; Nuclear Translocation; Organoids; Outcome; Pathway interactions; Patients; Perfusion; Pharmaceutical Preparations; Pharmacology; Phase; Phenotype; Primary Neoplasm; Prognosis; Proteins; RNA; RNA Degradation; Radio; Randomized; Regulation; Repression; Resistance; Sampling; Science; Stress; T-Lymphocyte; Testing; The Cancer Genome Atlas; Tissues; Toxic effect; Tumor Immunity; Tumor-infiltrating immune cells; Variant; Western Blotting; anti-cancer; base; brain tissue; cancer cell; checkpoint therapy; cranium; density; efficacy evaluation; environmental stressor; epithelial to mesenchymal transition; genetic manipulation; immune checkpoint; immune checkpoint blockade; immune checkpoint blockers; improved outcome; in vivo; intravital microscopy; mRNA Transcript Degradation; malignant breast neoplasm; mechanical force; mouse model; phase III trial; programmed cell death ligand 1; receptor; recruit; response; stemness; stress granule; therapy resistant; transcriptome; transcriptome sequencing; tumor; tumor growth

PROJECT ABSTRACT Patients with glioblastoma multiforme (GBM) have poor prognosis and limited treatment options. Immune checkpoint therapies, which have shown dramatic benefits in other cancers, have failed to improve outcomes in GBM patients in all randomized phase III trials. Brain tumors generate mechanical forces as they grow in the confined space of the cranium, and we have shown that these physical forces affect cell viability and phenotype (Nature Biotechnology 1997, PNAS 2012, Nature Biomedical Engineering 2016, 2019, Science 2020). Our preliminary results indicate that compressive forces similar to those in brain tumors are sufficient to upregulate stress granule protein G3BP2 as well as genes associated with epithelial-mesenchymal transition (EMT), stemness and the immune checkpoints. Furthermore, we have shown G3BP2 regulates cancer cell stemness in breast cancer (PNAS 2017). Thus, we hypothesize that mechanical stresses in the GBM environment contribute to GBM stemness and immunosuppression, and that the pathways involved can be targeted to enhance tumor killing. In this project, we will dissect the stress-induced pathways involved in mechanical regulation of stemness and immunosuppression in GBM. We will then block these pathways in orthotopic, immunocompetent mouse models of GBM to enhance immunotherapy. The overall goal of the study is to identify new strategies and targets for amplifying anti-tumor immunity based on mechanobiological control mechanisms.

项目摘要 多形性胶质母细胞瘤（GBM）患者预后较差，治疗选择有限。免疫 检查点疗法在其他癌症中显示出巨大的益处，但未能改善以下癌症的结果 所有随机 III 期试验中的 GBM 患者。脑肿瘤在生长时会产生机械力 颅骨的有限空间，我们已经证明这些物理力会影响细胞活力和表型 （《自然生物技术》1997 年，《美国国家科学院院刊》2012 年，《自然生物医学工程》2016 年、2019 年，《科学》2020 年）。我们的 初步结果表明，类似于脑肿瘤的压缩力足以上调 应激颗粒蛋白 G3BP2 以及与上皮间质转化 (EMT) 相关的基因， 干性和免疫检查点。此外，我们已经证明 G3BP2 调节癌细胞干性 乳腺癌（PNAS 2017）。因此，我们假设 GBM 环境中的机械应力 有助于 GBM 干性和免疫抑制，并且所涉及的途径可以针对 增强肿瘤杀伤作用。在这个项目中，我们将剖析机械中涉及的应力诱导途径 GBM 干性和免疫抑制的调节。然后我们将在原位阻断这些途径， GBM免疫活性小鼠模型可增强免疫治疗。该研究的总体目标是确定 基于机械生物学控制机制的增强抗肿瘤免疫力的新策略和目标。