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: 10696949
• 负责人: Rakesh K. Jain
• 金额: $ 61.13万
• 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/10696949
• 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; Epithelium; Exposure to; G3BP1 gene; Genes; Genetic; Genetic Transcription; Glioblastoma; Goals; Growth; Human; Hypoxia; ITIM; Immune; Immune response; Immune system; Immunity; 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; Phase; Phenotype; Primary Neoplasm; Prognosis; Proteins; RNA; RNA Degradation; Radio; Randomized; Receptor Inhibition; Regulation; Repression; Resistance; Sampling; Science; Stress; T-Lymphocyte; Testing; The Cancer Genome Atlas; Tissues; Toxic effect; Tumor Immunity; Variant; Western Blotting; anti-cancer; brain tissue; cancer cell; checkpoint therapy; cranium; density; efficacy evaluation; environmental stressor; epithelial to mesenchymal transition; genetic manipulation; immune cell infiltrate; immune checkpoint; immune checkpoint blockade; immune checkpoint blockers; improved outcome; in vivo; intravital microscopy; mRNA Transcript Degradation; malignant breast neoplasm; mechanical force; mouse model; pharmacologic; phase III trial; programmed cell death ligand 1; 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 所有随机III期试验中的GBM患者。脑肿瘤在大脑中生长时会产生机械力。 我们已经证明，这些物理力量会影响细胞的活力和表型， （Nature Biotechnology 1997，PNAS 2012，Nature Biomedical Engineering 2016，2019，Science 2020）。我们 初步结果表明，类似于脑肿瘤中的压力足以上调 应激颗粒蛋白G3 BP 2以及与上皮-间质转化（EMT）相关的基因， 干细胞和免疫检查点此外，我们已经表明G3 BP 2调节癌细胞的干细胞性， 乳腺癌（PNAS 2017）。因此，我们假设在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靶向于 增强肿瘤杀伤。在这个项目中，我们将剖析涉及机械应力诱导的途径， 调节GBM中的干性和免疫抑制。我们将阻断这些通路， GBM的免疫活性小鼠模型，以增强免疫治疗。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的新策略和靶点。

项目成果

A Phase I Trial of TB-403 in Relapsed Medulloblastoma, Neuroblastoma, Ewing Sarcoma, and Alveolar Rhabdomyosarcoma.

• DOI: 10.1158/1078-0432.ccr-22-1169
• 发表时间: 2022-09-15
• 期刊: CLINICAL CANCER RESEARCH
• 影响因子: 11.5
• 作者: Saulnier-Sholler, Giselle;Duda, Dan G.;Bergendahl, Genevieve;Ebb, David;Snuderl, Matija;Laetsch, Theodore W.;Michlitsch, Jennifer;Hanson, Derek;Isakoff, Michael S.;Bielamowicz, Kevin;Kraveka, Jacqueline M.;Ferguson, William;Carmeliet, Peter;De Deene, A.;Gijsen, Lore;Jain, Rakesh K.
• 通讯作者: Jain, Rakesh K.

Towards principled design of cancer nanomedicine to accelerate clinical translation.

• DOI: 10.1016/j.mtbio.2022.100208
• 发表时间: 2022-01
• 期刊: Materials today. Bio
• 作者: Souri M;Soltani M;Moradi Kashkooli F;Kiani Shahvandi M;Chiani M;Shariati FS;Mehrabi MR;Munn LL
• 通讯作者: Munn LL

Computational simulations of tumor growth and treatment response: Benefits of high-frequency, low-dose drug regimens and concurrent vascular normalization.

• DOI: 10.1371/journal.pcbi.1011131
• 发表时间: 2023-06
• 期刊: PLoS computational biology
• 影响因子: 4.3

Inhibition of CXCR4 Enhances the Efficacy of Radiotherapy in Metastatic Prostate Cancer Models.

CXCR4的抑制增强了放射疗法在转移性前列腺癌模型中的疗效。

• DOI: 10.3390/cancers15041021
• 发表时间: 2023-02-06
• 期刊: Cancers
• 影响因子: 5.2