“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 –

• 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
• 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

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)的耐药性限制了患者的生存 最常见的成人脑癌，胶质母细胞瘤(GBM)，至12-18个月。尽管在其他领域取得了可喜的成果 对于癌症，GBM中强有力的免疫抑制也限制了对免疫检查点抑制剂的反应 (ICIS)。间充质改变与基底膜肿瘤微环境(TME)的相互作用 免疫抑制分别增强了对化疗和免疫治疗的抵抗力。因此，a GBM的引人注目的治疗策略是同时重新编程间充质和免疫 抑制TMES，加强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的双吲哚配体(CDIMs)。 对NR4A1和NR4A2具有很强的双重拮抗作用，体内毒性可忽略不计，其中6种表现为NM 两个感受器的Kds范围。基于基因的NR4A 1和2功能丧失强烈激活抗癌 通过逆转T细胞耗竭的免疫反应，而T细胞耗竭是导致GBM不良ICI反应的基础。此外, NR4A1/2促进了其他癌症中的EMT，从而导致了化疗放射抵抗。最后，高水平的 GBM中NR4A1/2的表达与常规治疗后患者生存率下降密切相关 治疗。因此，我们建议检验这样的假设，即CDIM抑制NR4A1/2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CDIMs抑制PD-L1和Twist1的表达，逆转免疫抑制的髓系和T细胞 细胞表型与延长实验性肾小球系膜细胞存活。我们将通过i)确定铅来检验我们的假设 双重NR4A1/2 CDIM化合物对恶性和间叶性GBM细胞特性的抑制作用 (增殖、自我更新、侵袭)和体内功能障碍T细胞表型的逆转(目标1)，二 建立NR4A1/2 CDIMs对免疫抑制和间充质重新编程的功能影响 TME(目标2)和III)量化NR4A1/2 CDIMs增强小鼠ICI和SOC反应的作用 GBM同源基因模型，并确定PD-L1和Twist1在其作用机制中的作用(目标3)。 单独和联合TO的药效、药代动力学和临床前抗肿瘤活性的量化 TMZ-XRT和ICIS的护理标准有望确定候选CDIMs，供未来临床考虑 审判。通过应用强大的生物信息学工具，通过集成 ScRNAseq、CyTOF和IMC数据，这些研究有望揭示新的机制，通过这些机制 间充质和免疫抑制Tme相互作用协同驱动GBM的治疗耐药 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，拥有医疗专业知识 化学、神经肿瘤学、基底膜生物学和临床前建模，以及免疫肿瘤学。