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)在以下情况下发挥了优越的抗肿瘤作用 与维甲酸结合，一类维生素A代谢物。我们发现了一种新的肿瘤抑制基因-- 通过全基因组敲除策略与维甲酸干扰素诱导的死亡率-19(GRIM-19)相关。在我们的 最近在PNAS上发表的文章中，我们发现GRIM-19基因在 几种人类癌症，包括头颈部癌症和小鼠的Grim-19单等位基因缺失 增强对肿瘤形成的敏感性。我们证明了直接注射裸质粒 携带GRIM-19或表达GRIM-19的慢病毒进入肿瘤可强烈抑制肿瘤生长和 转移，表明其潜在的治疗作用。然而，作为一种可行的商业战略，我们将 重组表达含有蛋白转导结构域(PTD)的GRIM-19表达产物 治疗性的(rGRIM-19)，可以阻止癌细胞的生长。PTD结构域允许蛋白质跨 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杀死口腔 癌细胞，但不是正常细胞。根据我们令人信服的初步数据，我们假设rGRIM-19 将被证明是一种有效的控制肿瘤生长的生物疗法。为了检验这一假设， 我们将研究rGRIM-19在相关小鼠模型中治疗肿瘤的有效性。 头颈部鳞癌(HNSCC)。为此，我们生成了一个有条件的严峻- 19 KO小鼠，并建立了GRIM-19缺陷患者来源的异种移植(PDX)模型。我们将使用 KO小鼠产生口腔肿瘤，并确定rGRIM-19治疗这些肿瘤是否会逆转 致癌基因标记并在体内强制抑制肿瘤生长。将采取类似的方法来处理 用PDX模型研究rGRIM-19对人体内肿瘤的影响。在这项研究结束时，我们预计 开发一种治疗人类肿瘤的蛋白质疗法。

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.