Targeting eEF2 with the protein translation elongation inhibitor SVC112 in head and neck squamous cancer

使用蛋白质翻译延伸抑制剂 SVC112 靶向治疗头颈鳞状细胞癌中的 eEF2

基本信息

批准号：
10268847
负责人：
Antonio Jimeno
金额：
$ 36.67万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10268847
关键词：
Address Affect Biological Assay Biological Markers Cancer Model Cancer Patient Cancer Prognosis Cancer cell line Cell Communication Cell Cycle Cell model Cells Clinical Trials Colorado Companions Complex Cyclin D1 Data Disease Dose Drug Kinetics Drug resistance Evaluation FDA approved FRAP1 gene Failure Fibrinogen Genes Goals Growth Head and Neck Cancer Head and Neck Squamous Cell Carcinoma Head and neck structure Home Human Human Papillomavirus Hypoxia Immune Immune Evasion Immune Targeting Immunity Immunologic Surveillance Immunotherapy In Vitro Infiltration Internal Ribosome Entry Site Ligands Malignant Neoplasms Measures Mediating Messenger RNA Minority Modality Modeling Molecular Target Mus Mutation Oncogenic Oncoproteins Outcome Papillomavirus Transforming Protein E6 Pathway interactions Patients Pharmaceutical Preparations Pharmacology Predictive Value of Tests Predisposition Production Property Protein Biosynthesis Proteins Proteome Proteomics Proto-Oncogene Proteins c-myc Radiation therapy Relapse Reporting Resistance Rest Ribosomes Sampling Signal Transduction Stress T-Lymphocyte Testing Therapeutic Therapeutic Index Tissue Banks Tissues Toxic effect Toxicity Tests Translations Treatment Efficacy Treatment Failure Tumor Bank Tumor-infiltrating immune cells Work base cancer cell cancer therapy efficacy testing fitness gene product humanized mouse in vivo in vivo Model inhibitor/antagonist mouse model neoplastic cell novel therapeutics patient derived xenograft model pembrolizumab predictive marker programmed cell death ligand 1 programmed cell death protein 1 protein expression ribosome profiling small molecule stemness synergism tool transcription factor tumor tumor growth tumor microenvironment tumor progression

项目摘要

SUMMARY. Radiation therapy (RT) and immunotherapy with PD-1 inhibitors are used in early and relapsed head and neck squamous cell cancers (HNSCC), respectively; RT failures are common, and most patients do not respond to PD-1 inhibition. Both impact the tumor microenvironment (TME), but studying the TME is limited by the availability of models with human immune cells. PI3K/mTOR signaling regulates protein synthesis through transcription factors such as Myc or SOX2, that dictate growth, invasion, and drug resistance in HNSCC. SVC112 is a fully synthetic small molecule that inhibits protein synthesis at the elongation step by inhibiting eEF2. SVC112 had greater effect on cancer over non-cancer cells, and was more potent and selective than homoharringtonin (HHT), an FDA-approved translation elongation inhibitor. Cancer cells had higher eEF2 than non-cancer cells, and the most susceptible strain had the highest eEF2 expression. SVC112 depleted SOX2, Myc, and Cyclin D1 in HNSCC cells at concentrations that had minimal effect on the rest of the proteome. SVC112 decreased spheres in vitro, reduced tumor growth in vivo in patient-derived xenografts (PDX), and induced tumor regression when given with RT in three out of four PDX models. SVC112 also reduced the E6 oncoprotein in human papillomavirus-driven cells. Lastly, SVC112 decreased PD-1 ligand (PD-L1) resulting in decreased PD-L1:PD-1 interactions leading to increased sphere T cell invasion, while having no effect on T cell fitness or function. Thus, SVC112 can target multiple key pathways (SOX2, Myc, PD-L1), and can influence the TME to reverse immune evasion. To test SVC112’s therapeutic potential in HNSCC, several unique tools will be used including 1) spheres containing cancer cells and T cells (iSpheres) that enable studying TME interactions and immunotherapy in vitro, 2) syngeneic mouse models of HNSCC, and 3) humanized mouse (HM) models, developed by the PI, that enable studying TME interactions and immunotherapy in vivo. The hypothesis that SVC112’s discriminating effect is due to selective depletion of key proteins will be tested by ribosome profiling (to identify mRNA targets) and proteomics analysis (to identify proteins targets). Then, we will test the mechanism of SVC112 synergy with RT, and if the modulation of the TME by SVC112 will further enhance RT efficacy. Lastly, the hypothesis that reduction of PD-L1 by SVC112 in HNSCC will alter the tumor-immune interaction will be tested by defining the effect of SVC112 on the expression of proteins critical for the TME, T cell tumor infiltration, and cancer-immune crosstalk. The effect of SVC112 on T cell fitness and function will be examined, aiding SVC112 translation. We will assess SVC112 and PD-1 inhibition in iSphere and HM models, and explore their efficacy when both are combined. Lastly, we will test the predictive value of eEF2 in SVC112 susceptibility, and we will assess eEF2 expression in human tumors, to enable identifying a companion biomarker to SVC112, using a HNSCC tissue bank with 1,250 patient cases. This project will propel the translation of SVC112, a drug discovered in Colorado, by dissecting the basis for its effect, studying its toxicity, and testing predictive biomarkers to aid clinical trials.

摘要：放射治疗 (RT) 和 PD-1 抑制剂免疫治疗适用于早期和复发患者。头颈鳞状细胞癌 (HNSCC) 分别是放疗失败的常见情况，而且大多数患者都会出现这种情况；对 PD-1 抑制没有反应两者都会影响肿瘤微环境 (TME)，但对 TME 的研究有限。 PI3K/mTOR 信号传导通过人类免疫细胞模型的可用性来调节蛋白质合成。 Myc 或 SOX2 等转录因子决定了 SVC112 的生长、侵袭和耐药性。是一种完全合成的小分子，通过抑制 SVC112 来抑制延伸步骤中的蛋白质合成。与非癌细胞相比，对癌症的影响更大，并且比高三尖杉酯碱更有效、更具选择性 (HHT)，一种 FDA 批准的翻译延伸抑制剂，癌细胞的 eEF2 高于非癌细胞，最易受影响的菌株具有最高的 SVC112 缺失 SOX2、Myc 和 Cyclin D1 表达。在 HNSCC 细胞中，浓度对 SVC112 的其余部分影响最小。体外球体，减少体内患者来源的异种移植物（PDX）中的肿瘤生长，并诱导肿瘤消退当在四分之三的 SVC112 模型中给予 RT 时，也减少了人类的 E6 癌蛋白。最后，SVC112 减少 PD-1 配体 (PD-L1)，导致 PD-L1:PD-1 减少。相互作用导致 T 细胞侵袭增加，同时对 T 细胞的适应性或功能没有影响。 SVC112可以靶向多个关键通路（SOX2、Myc、PD-L1），并可以影响TME逆转免疫为了测试 SVC112 在 HNSCC 中的治疗潜力，将使用几种独特的工具，包括 1) 球体。含有癌细胞和 T 细胞 (iSpheres)，可以在体外研究 TME 相互作用和免疫疗法， 2) HNSCC 的同基因小鼠模型，以及 3) 由 PI 开发的人源化小鼠 (HM) 模型，使研究 TME 相互作用和体内免疫治疗 SVC112 的区分作用的假设是由于关键蛋白质的选择性耗尽，将通过核糖体分析（以识别 mRNA 目标）进行测试，并且然后，我们将测试SVC112与RT的协同作用机制， SVC112 对 TME 的调节是否会进一步增强 RT 疗效最后，假设如下。 SVC112 在 HNSCC 中减少 PD-L1 将改变肿瘤免疫相互作用，将通过定义 SVC112 对 TME、T 细胞肿瘤浸润和癌症免疫至关重要的蛋白质表达的影响我们将检查 SVC112 对 T 细胞适应性和功能的影响，以帮助 SVC112 翻译。将评估 iSphere 和 HM 模型中的 SVC112 和 PD-1 抑制作用，并探讨两者均有效时的功效最后，我们将测试eEF2对SVC112敏感性的预测价值，并评估eEF2。在人类肿瘤中表达，以便能够使用 HNSCC 组织识别 SVC112 的伴随生物标志物拥有 1,250 例患者病例的银行该项目将推动 SVC112（一种在科罗拉多州发现的药物）的转化。通过剖析其作用的基础、研究其毒性并测试预测生物标志物以帮助临床试验。