权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

“Pharmacologic targeting of NR4A1 and NR4A2 to activate glioblastoma treatment response”

– NR4A1 和 NR4A2 的药理学靶向激活胶质母细胞瘤治疗反应 –

基本信息

批准号：
10744524
负责人：
Andrei M Mikheev
金额：
$ 50.34万
依托单位：
METHODIST HOSPITAL RESEARCH INSTITUTE
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：
2023-09-19 至 2028-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10744524
关键词：
Adoptive Transfer Adult Automobile Driving Bioinformatics Biological Assay Biology Cancer Model Carcinoma Cell Line Cell Proliferation Cell physiology Cells Cessation of life Clinical Trials Data Drug Kinetics Exhibits Future Gene Expression Genes Genetic Glioblastoma Goals Human IL8 gene Immune Immune Evasion Immune checkpoint inhibitor Immune response Immunooncology Immunosuppression Immunotherapy Indoles Infiltration Invaded Lead Ligands Macrophage Malignant - descriptor Malignant Neoplasms Malignant neoplasm of brain Measures Mediating Mesenchymal Mesenchymal Cell Neoplasm Modeling Molecular Mus Myeloid Cells Myeloid-derived suppressor cells NR4A1 gene NR4A2 gene Nuclear Orphan Receptor Orphan Nuclear Receptor Gene Outcome Patients Pharmaceutical Chemistry Pharmaceutical Preparations Phenotype Pre-Clinical Model Preclinical Testing Production Proliferating Property Radiation therapy Receptor Inhibition Regulation Regulatory T-Lymphocyte Resistance Role Series Signal Transduction T cell differentiation T-Lymphocyte TWIST1 gene Testing Therapeutic Toxic effect Tumorigenicity antagonist anti-cancer bioinformatics tool candidate identification checkpoint therapy chemoradiation conventional therapy cytokine cytotoxicity exhaust exhaustion improved in vivo in vivo evaluation knock-down loss of function migration multidisciplinary neoplastic cell neuro-oncology novel novel strategies novel therapeutics pharmacologic pre-clinical programmed cell death ligand 1 programs radiation resistance receptor receptor expression response self-renewal single-cell RNA sequencing standard of care stem cell self renewal stemness temozolomide therapy resistant treatment response tumor tumor growth tumor microenvironment tumor-immune system interactions

项目摘要

Resistance to standard of care (SOC) temozolomide (TMZ) and radiation treatment (XRT) limits survival of the most common adult brain cancer, glioblastoma (GBM), to 12-18 months. Despite promising results in other cancers, robust immunosuppression in GBM has also limited the responses to immune checkpoint inhibitors (ICIs). Reciprocal interactions in the GBM tumor microenvironment (TME) between mesenchymal changes and immunosuppression enhance resistance to chemoradiation and immunotherapy, respectively. Therefore, a compelling therapeutic strategy for GBM is to concurrently reprogram the mesenchymal and immune suppressive TMEs and potentiate ICI and SOC therapy. The NR4A1 and NR4A2 orphan nuclear receptors are compelling targets to achieve this goal. We synthesized a series of novel bis-indole–derived ligands (CDIMs) with potent dual antagonism of NR4A1 and NR4A2 and negligible in vivo toxicity, of which six demonstrated nM range KDs for both receptors. Genetic based NR4A 1 and 2 loss of function strongly activates anti-cancer immune responses by reversing T-cell exhaustion which underlies poor ICI responses in GBM. In addition, NR4A1/2 promote EMT in other cancers which contributes to chemoradiation resistance. Finally, high levels of NR4A1/2 expression in GBM are strongly associated with decreased patient survival after conventional treatments. Therefore, we propose to test the hypothesis that CDIM inhibition of NR4A1/2 reprograms the GBM TME and potentiates ICI and TMZ/XRT responses. Further NR4A1/2 upregulates PD-L1 and TWISt1, key regulators of GBM immune suppression and mesenchymal phenotypes, respectively. Preliminary studies demonstrated that CDIMs inhibit PD-L1 and TWIST1 expression, reverse immune suppressive myeloid and T cell phenotypes and prolong survival of experimental GBMs. We will test our hypothesis by i) identifying lead dual NR4A1/2 CDIM compounds based on inhibition of malignant and mesenchymal GBM cell properties (proliferation, self-renewal, invasion) and reversal of dysfunctional T cell phenotypes in vivo (Aim 1), ii) establishing the functional impact of NR4A1/2 CDIMs to reprogram the immune suppressive and mesenchymal TME (Aim 2) and iii) quantifying the effects of NR4A1/2 CDIMs to potentiate ICI and SOC responses in mouse GBM syngeneic models and define the role of PD-L1 and TWIST1 in their mechanisms of action (Aim 3). Quantification of potency, pharmacokinetics and preclinical anti-tumor activity alone and in combination with to standard of care TMZ-XRT and ICIs is expected to identify candidate CDIMs for consideration in future clinical trials. Through application of powerful bioinformatic tools that model the cancer TME through integration of scRNAseq, cyTOF and IMC data, these studies are expected to shed new light on novel mechanisms by which mesenchymal and immune suppressive TMEs interact to coordinately drive treatment resistance in GBM through NR4A1/2. To achieve our goals, we assembled a unique multidisciplinary team with expertise in medicinal chemistry, neuro-oncology, GBM biology and preclinical modeling, and immuno-oncology.

对标准护理 (SOC) 替莫唑胺 (TMZ) 和放射治疗 (XRT) 的抵抗限制了患者的生存最常见的成人脑癌是胶质母细胞瘤 (GBM)，发病年龄为 12-18 个月。尽管在其他方面取得了可喜的成果癌症，GBM 中强大的免疫抑制也限制了对免疫检查点抑制剂的反应（ICIs）。 GBM肿瘤微环境（TME）中间充质变化和免疫抑制分别增强对放化疗和免疫治疗的抵抗力。因此，一个 GBM 引人注目的治疗策略是同时重新编程间充质和免疫细胞抑制 TME 并增强 ICI 和 SOC 治疗。 NR4A1 和 NR4A2 孤儿核受体是实现这一目标的紧迫目标。我们合成了一系列新型双吲哚衍生配体（CDIM）具有 NR4A1 和 NR4A2 的强效双重拮抗作用，体内毒性可忽略不计，其中 6 种表现出 nM 两种受体的 KD 范围。基于基因的 NR4A 1 和 2 功能丧失可强烈激活抗癌作用通过逆转 T 细胞耗竭来调节免疫反应，而 T 细胞耗竭是 GBM 中 ICI 反应不佳的基础。此外， NR4A1/2 促进其他癌症的 EMT，从而导致放化疗耐药。最后，高水平 GBM 中的 NR4A1/2 表达与常规治疗后患者生存率下降密切相关治疗。因此，我们建议检验以下假设：CDIM 抑制 NR4A1/2 会重新编程 GBM TME 并增强 ICI 和 TMZ/XRT 反应。 NR4A1/2 进一步上调 PD-L1 和 TWISt1，分别是 GBM 免疫抑制和间充质表型的关键调节因子。初步研究证明 CDIM 抑制 PD-L1 和 TWIST1 表达，逆转免疫抑制性骨髓和 T 细胞表型并延长实验性 GBM 的存活时间。我们将通过 i) 识别铅来检验我们的假设基于抑制恶性和间充质 GBM 细胞特性的双重 NR4A1/2 CDIM 化合物（增殖、自我更新、入侵）和体内功能失调的 T 细胞表型的逆转（目标 1），ii) 确定 NR4A1/2 CDIM 对免疫抑制和间充质细胞重编程的功能影响 TME（目标 2）和 iii）量化 NR4A1/2 CDIM 对增强小鼠 ICI 和 SOC 反应的影响 GBM 同系模型并定义 PD-L1 和 TWIST1 在其作用机制中的作用（目标 3）。单独和联合使用的效力、药代动力学和临床前抗肿瘤活性的量化护理标准 TMZ-XRT 和 ICI 预计将确定候选 CDIM，供未来临床考虑试验。通过应用强大的生物信息工具，通过整合以下各项来模拟癌症 TME scRNAseq、cyTOF 和 IMC 数据，这些研究有望为新机制提供新的线索间充质和免疫抑制性 TME 相互作用，通过以下方式协调驱动 GBM 的治疗抵抗： NR4A1/2。为了实现我们的目标，我们组建了一支独特的多学科团队，拥有医学专业知识化学、神经肿瘤学、GBM 生物学和临床前建模以及免疫肿瘤学。