MALT1 protease as a regulator of anti-tumor immunity and tumor progression in diffuse midline glioma

MALT1 蛋白酶作为弥漫性中线神经胶质瘤抗肿瘤免疫和肿瘤进展的调节剂

基本信息

批准号：
10750167
负责人：
Hannah Butterfield
金额：
$ 5.27万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10750167
关键词：
Affect Astrocytes BCL10 gene Biological Response Modifiers Blood - brain barrier anatomy Brain Brain Stem Brain region Categories Cell Survival Cells Childhood Childhood Brain Neoplasm Childhood Brain Stem Neoplasm Clinical Trials Coculture Techniques Complex Cytoplasmic Protein Data Development Diagnosis Excision Fostering Genes Genetic Transcription Glioblastoma Glioma H3 K27M mutation Histone H3.3 Immune Immunity Immunofluorescence Immunologic In Vitro Individual Infiltration Invaded Laboratories Location Lymphocyte Depletion Malignant - descriptor Malignant Childhood Neoplasm Malignant Neoplasms Mentorship Microglia Midbrain structure Modeling Molecular Mucosa- associated lymphoid tissue lymphoma translocation protein-1 Mus Myelogenous NF-kappa B Nature Neoplasms Operative Surgical Procedures Pathogenesis Patients Peptide Hydrolases Pharmacologic Substance Phenothiazines Physicians Play Point Mutation Pontine structure Proliferating Protease Inhibitor Proteins Radiation Radiation therapy Research Personnel Research Training Role Sampling Scientist Series Signal Transduction Structure Techniques Testing Therapeutic Training Tumor Immunity Tumor-associated macrophages Tumor-infiltrating immune cells Wild Type Mouse cancer cell cancer type career cell killing cell motility diffuse midline glioma effective therapy epigenome experience experimental study immune activation immune cell infiltrate improved inhibitor migration mouse model new therapeutic target novel novel therapeutic intervention pediatric patients pharmacologic protein complex response scaffold single-cell RNA sequencing standard care translational therapeutics tumor tumor growth tumor microenvironment tumor progression tumor-immune system interactions

项目摘要

PROJECT SUMMARY/ABSTRACT H3K27M-mutant diffuse midline glioma (DMG) is a devastating pediatric brain tumor. Surgical resection is difficult because these tumors are in delicate midbrain/brainstem locations and infiltrate into critical structures. Despite decades of clinical trials, H3K27M-mutant DMG is considered uniformly fatal, with a median overall survival of 9-11 months. Radiation therapy, which itself is highly toxic to the developing pediatric brain, extends survival by 2-3 months. Therefore, the development of safe and effective therapies for DMG is of utmost importance. I propose to evaluate the effect of inhibiting MALT1 on the pathogenesis of H3K27M-mutant DMG. MALT1 is the effector molecule of the CARMA/CARD-BCL10-MALT1 (CBM) signalosome, a cytoplasmic protein complex that drives downstream pro-survival NF-kB transcriptional activity. MALT1 possesses both scaffolding and protease activities. Our laboratory and others have demonstrated that MALT1 protease activity promotes cancer cell viability, proliferation, and migration/invasion in multiple cancer types. In addition to its role within cancer cells, MALT1 is also a critical regulator of immune cell responses, and our laboratory is investigating the impact of MALT1 protease in the tumor microenvironment (TME) of high-grade glioma. Based on my preliminary data, I hypothesize that inhibiting MALT1 proteolytic activity could provide dual benefit in H3K27M-mutant DMG, both via the direct effects of inhibiting MALT1 within the cancer cells and via the effects of inhibiting MALT1 protease within immune cells of the TME to promote anti-tumor immune activation. In Aim 1 of this proposal, we will evaluate the influence of MALT1 protease activity on the H3K27M-mutant DMG TME. Experimental techniques utilized in this aim will include use of murine models, single cell RNA sequencing, and multispectral immunofluorescence. In Aim 2 of this proposal, we will evaluate the impact of MALT1 protease inhibition on malignant features of H3K27M-mutant DMG cells, using a series of in vitro analyses. Finally, in Aim 3, we will analyze the impact of MALT1 protease inhibition, with or without radiation, in our orthotopic/syngeneic H3K27M-mutant DMG model. Overall, this project evaluates inhibition of MALT1 protease as a potential therapeutic approach for H3K27M- mutant DMG. Completion of this proposal will provide me with exceptional research training by an outstanding team of scientists and physician-scientists. This training experience will prepare me for a career as a physician- scientist who studies the molecular underpinnings of pediatric cancers to develop new and improved treatments.

项目摘要/摘要 H3K27M突变的弥漫性中线神经胶质瘤（DMG）是毁灭性的小儿脑肿瘤。手术切除很困难因为这些肿瘤位于细腻的中脑/脑干位置，并渗入关键结构。尽管数十年的临床试验，H3K27M突变的DMG被认为是统一致命的，中位总生存期为 9-11个月。放射疗法本身对发育中的小儿大脑剧毒，将生存扩展到 2-3个月。因此，开发用于DMG的安全有效疗法至关重要。我建议评估抑制MALT1对H3K27M突变DMG发病机理的影响。 Malt1是 CARMA/CARD-BCL10-MALT1（CBM）信号体的效应子分子，一种细胞质蛋白质复合物驱动下游促生存的NF-KB转录活性。 MALT1具有脚手架和蛋白酶活动。我们的实验室和其他人已经证明MALT1蛋白酶活性促进了癌细胞多种癌症类型的生存力，增殖和迁移/侵袭。除了它在癌细胞中的作用外， MALT1还是免疫细胞反应的关键调节剂，我们的实验室正在研究高级神经胶质瘤的肿瘤微环境（TME）中的MALT1蛋白酶。根据我的初步数据，我假设抑制MALT1蛋白水解活性可以在H3K27M突变的DMG中提供双重益处通过抑制癌细胞内MALT1的直接影响以及抑制MALT1蛋白酶的作用在TME的免疫细胞内，以促进抗肿瘤免疫激活。在该提案的目标1中，我们将评估MALT1蛋白酶活性对H3K27M突变DMG的影响 TME。在此目标中使用的实验技术将包括使用鼠模型，单细胞RNA测序，和多光谱免疫荧光。在该提案的目标2中，我们将评估MALT1蛋白酶的影响使用一系列体外分析，对H3K27M突变DMG细胞的恶性特征的抑制作用。最后，目标 3，我们将分析在我们的原位/合成性中，MALT1蛋白酶抑制，无论是否没有辐射， H3K27M突变DMG模型。总体而言，该项目评估了对MALT1蛋白酶的抑制作用，作为H3K27M-的潜在治疗方法突变DMG。该建议的完成将为我提供杰出的研究培训科学家和医师科学家团队。这种培训经验将使我为医生的职业做好准备 - 研究儿科癌症分子基础以开发新的和改进的治疗方法的科学家。