GRIM19 for head and neck cancer therapy

项目摘要 许多临床和临床前研究表明，干扰素（IFN）发挥上级抗肿瘤作用，当 与维生素A代谢物类维生素A结合。我们发现了一个新的肿瘤抑制基因- 通过全基因组敲除策略与类视黄醇-IFN诱导的死亡率-19（GRIM-19）相关。在我们 最近发表在PNAS上，我们已经表明GRIM-19基因在人的大脑中被抑制或突变， 几种人类癌症，包括头部和颈部的癌症，以及小鼠中Grim-19的单等位基因丢失 增强对肿瘤发生的易感性。我们证明直接给予裸质粒 将GRIM-19或表达GRIM-19的慢病毒携带到肿瘤中强烈抑制肿瘤生长， 转移，表明其潜在的治疗效用。然而，作为一个可行的商业策略，我们将 重组表达含有蛋白转导结构域（PTD）的GRIM-19以开发有效蛋白 治疗（rGRIM-19），可以阻止癌细胞的生长。PTD结构域允许蛋白质跨膜转移。 细胞膜。我们已经生产了rGRIM-19并进行了纯化。在我们的初步研究中，rGRIM-19可以杀死口服 癌细胞而不是正常细胞根据我们令人信服的初步数据，我们假设rGRIM-19 将被证明是控制肿瘤生长的有效生物治疗剂。为了验证这个假设， 我们将研究rGRIM-19在相关的小鼠模型中治疗肿瘤的治疗效用， 头颈部鳞状细胞癌。为此，我们生成了一个条件严峻- 19 KO小鼠，并且还开发了GRIM-19缺陷型患者来源的异种移植物（PDX）模型。我们将使用 KO小鼠产生口腔肿瘤，并确定用rGRIM-19治疗这些肿瘤是否会逆转肿瘤的生长。 致癌基因标签和增强体内肿瘤生长抑制。将采取类似的方法， PDX模型以研究rGRIM-19对体内人肿瘤的作用。在本研究结束时，我们希望 开发一种治疗人类肿瘤的蛋白质治疗剂。

Project Summary Many clinical and preclinical studies demonstrated that interferons (IFNs) exert a superior anti-tumor effect, when combined with retinoids, a class of vitamin-A metabolites. We identified a novel tumor suppressor Gene- associated with Retinoid-IFN induced Mortality-19 (GRIM-19) by a genome-wide knockdown strategy. In our recent publication in the PNAS, we have shown that GRIM-19 gene is either suppressed or mutated in several human cancers, including those of head and neck, and a mono-allelic loss of Grim-19 in mice enhances susceptibility to tumorigenesis. We demonstrated that direct administration of naked plasmids carrying GRIM-19 or lentiviruses expressing GRIM-19 into tumors robustly suppressed tumor growth and metastases, indicating its potential therapeutic utility. However, as a viable commercial strategy, we will recombinantly express GRIM-19 containing a protein transduction domain (PTD) to develop a potent protein therapeutic (rGRIM-19) that could block cancer cell growth. The PTD domain allows transfer of protein across the cell membrane. We already produced rGRIM-19 and purified. In our preliminary studies, rGRIM-19 kills oral cancer cells, but not normal cells. Based on our compelling preliminary data we hypothesize that rGRIM-19 will prove to be an effective biological therapeutic for controlling tumor growth. To test this hypothesis, we will investigate the therapeutic utility of rGRIM-19 for treating tumors in a relevant mouse model of head and neck squamous cell carcinoma (HNSCC). For this purpose, we have generated a conditional Grim- 19 KO mouse and also developed GRIM-19 deficient patient-derived xenograft (PDX) models. We will use the KO mice to generate oral tumors and determine if treatment of these tumors with rGRIM-19 would reverse the oncogenic gene signatures and enforce tumor growth suppression in vivo. A similar approach will be taken with the PDX models to study the effect of rGRIM-19 on human tumors in vivo. At the end of this study we expect to develop a protein therapeutic for treating human tumors.