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

• 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
• 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

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.

总结。早期和复发患者采用放射治疗(RT)和PD-1抑制剂免疫治疗 分别为头颈部鳞状细胞癌(HNSCC)；RT失败很常见，大多数患者也是如此 对PD-1抑制无反应。两者都影响肿瘤微环境(TME)，但对TME的研究有限 人类免疫细胞模型的可获得性。PI3K/mTOR信号转导途径调节蛋白质合成 转录因子，如Myc或SOX2，决定HNSCC的生长、侵袭和耐药性。SVC112 是一种完全合成的小分子，通过抑制eEF2来抑制伸长阶段的蛋白质合成。SVC112 对癌症的影响比非癌细胞更大，比高三尖杉酯碱更有效和更有选择性 (HHT)，一种FDA批准的翻译延长抑制剂。癌细胞的eEF2高于非癌细胞， 最敏感品系的eEF2表达水平最高。SVC112耗尽SOX2、Myc和Cyclin D1 在HNSCC细胞中，对蛋白质组其余部分影响最小的浓度。SVC112减少 体外球体，减少患者来源的异种移植(PDX)体内的肿瘤生长，并诱导肿瘤消退 当给予RT时，四个PDX模型中有三个。SVC112还降低了人类E6癌蛋白 乳头瘤病毒驱动的细胞。最后，SVC112使PD-1配体(PD-L1)减少，导致PD-L1：PD-1减少 相互作用导致球形T细胞侵袭增加，而对T细胞健康或功能没有影响。因此， SVC112可以靶向多个关键通路(SOX2、Myc、PD-L1)，并可影响TME逆转免疫 逃避。为了测试SVC112的S在鼻咽癌中的治疗潜力，将使用几种独特的工具，包括1)球体 含有癌细胞和T细胞(ISphes)，能够在体外研究TME相互作用和免疫治疗， 2)HNSCC同基因小鼠模型，3)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S辨证作用为 由于关键蛋白的选择性耗尽，将通过核糖体图谱(以确定mRNA靶标)和 蛋白质组学分析(以确定蛋白质靶标)。然后，我们将测试SVC112与RT的协同作用机制， 而SVC112对TME的调节是否会进一步增强RT的疗效。最后，假设 在HNSCC中，SVC112降低PD-L1会改变肿瘤-免疫相互作用，将通过定义 SVC112对TME、T细胞肿瘤侵袭及肿瘤免疫关键蛋白表达的影响 相声。我们将研究SVC112对T细胞适合性和功能的影响，以帮助翻译SVC112。我们 将在IVERE和HM模型中评估SVC112和PD-1的抑制作用，并探索当两者都是 加在一起。最后，我们将测试eEF2在SVC112易感性中的预测价值，并评估eEF2 在人类肿瘤中表达，以便能够使用HNSCC组织识别SVC112的伴随生物标记物 银行有1,250例患者。该项目将推动在科罗拉多州发现的药物SVC112的翻译， 通过剖析其效果的基础，研究其毒性，并测试预测生物标记物以帮助临床试验。