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“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.

对标准治疗（SOC）替莫唑胺（TMZ）和放射治疗（XRT）的耐药性限制了患者的生存期。最常见的成人脑癌，胶质母细胞瘤（GBM），到12-18个月。尽管在其他方面取得了可喜的成果，在癌症中，GBM中的强大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）中间充质变化与免疫抑制分别增强了对化疗和免疫治疗的抵抗力。因此令人信服的GBM治疗策略是同时重编程间充质和免疫细胞，抑制性TME并增强ICI和SOC治疗。NR 4A 1和NR 4A 2孤儿核受体是为实现这一目标而制定的强制性目标。我们合成了一系列新型的双吲哚衍生配体（CDIMs）具有NR 4A 1和NR 4A 2的强效双重拮抗作用，体内毒性可忽略不计，其中6个显示nM 两种受体的KD范围。基于遗传的NR 4A 1和2功能丧失强烈激活抗癌作用通过逆转T细胞耗竭（其是GBM中不良ICI应答的基础）来增强免疫应答。此外，本发明还提供了一种方法， NR 4A 1/2在其他癌症中促进EMT，这有助于化疗和放疗抗性。最后，高水平的 GBM中的NR 4A 1/2表达与常规化疗后患者存活率降低密切相关。治疗。因此，我们建议检验CDIM抑制NR 4A 1/2重编程NR 4A 1/2的假设。 GBM TME和增强ICI和TMZ/XRT反应。此外，NR 4A 1/2上调PD-L1和TWISt 1， 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TWIST 1表达，逆转免疫抑制性骨髓和T细胞细胞表型和延长实验GBM的存活。我们将通过i）识别铅基于抑制恶性和间充质GBM细胞特性的双重NR 4A 1/2 CDIM化合物（增殖、自我更新、侵袭）和体内功能失调的T细胞表型的逆转（目的1），ii）建立NR 4A 1/2 CDIM重编程免疫抑制和间充质细胞的功能影响， iii）量化NR 4A 1/2 CDIM增强小鼠ICI和SOC应答的作用 GBM同基因模型，并定义PD-L1和TWIST 1在其作用机制中的作用（目的3）。单独和与以下药物组合的效力、药代动力学和临床前抗肿瘤活性的定量：标准治疗TMZ-XRT和ICI有望识别候选CDIM，供未来临床研究考虑。审判通过应用强大的生物信息学工具，通过整合 scRNAseq、cyTOF和IMC数据，这些研究有望揭示新的机制，间充质和免疫抑制性TME相互作用，通过以下途径协调驱动GBM中的治疗抗性： NR4A1/2。为了实现我们的目标，我们组建了一个独特的多学科团队，拥有医学方面的专业知识，化学、神经肿瘤学、GBM生物学和临床前建模以及免疫肿瘤学。