Targeting Oncogenic KRAS with Brush-Architectured Poly(ethylene glycol)-DNA Conjugates

项目概要/摘要 KRAS的突变形式是人类肿瘤的关键驱动因素，但仍然难以治疗干预 尽管经过了三十多年的研究直接或间接抑制KRAS功能的临床尝试 两种方法的结果都不令人满意。开发小分子KRAS抑制剂的难度已经增加， 针对致癌基因的替代方法的重要性。一种这样的策略涉及治疗性核酸 酸，这使得有可能耗尽靶蛋白，这是难以对付的传统药物模式。我们 已经开发了一种新形式的核酸治疗剂，称为pacDNA，它大大增强了 通过提高体内稳定性、加速细胞摄取和改善抗肿瘤活性， 血浆药代动力学和肿瘤蓄积，允许使用比 常规方法。pacDNA还抑制了几乎所有与传统核酸相关的副作用。 通过减少不需要的核酸-蛋白质相互作用来治疗酸性药物。在这一建议中，我们的目标是建立在我们的 有希望的初步结果，并获得更深入的了解细胞生物学的pacDNA方面的细胞 摄取机制，细胞内运输，KRAS消耗和随后的细胞信号传导，并证明 在KRAS依赖性非小细胞肺癌细胞系和3D模型中的疗效。此外，我们会研究 pacDNA在晚期临床前肺癌模型中的主要药理学和抗肿瘤活性 原位肿瘤模型、患者来源的肿瘤模型和同基因遗传工程小鼠 模型（GEMM），并进行初步的体内安全性和耐受性研究。该项目的成果将是 一种安全有效的抗KRAS药物，可用于非小细胞肺癌的临床研究 癌症和潜在的其他癌症类别。

Project Summary/Abstract Mutant forms of KRAS are a key driver in human tumors but remains refractory to therapeutic intervention despite over three decades of research. Clinical attempts to directly or indirectly inhibit KRAS function have both yielded unsatisfactory results. The difficulty for developing small molecule KRAS inhibitors has heightened the importance of alternative methods targeting the oncogene. One such strategy involves therapeutic nucleic acids, which make it possible to deplete target proteins that are intractable to conventional drug modalities. We have developed a novel form of nucleic acid therapeutics, termed pacDNA, that substantially enhances the antitumor activity of nucleic acid drugs by elevating in vivo stability, accelerating cellular uptake, and improving plasma pharmacokinetics and tumor accumulation, allowing a much lower dosage to be used compared to conventional methods. The pacDNA also suppresses nearly all side effects associated with traditional nucleic acid drugs by reducing unwanted nucleic acid-protein interactions. In this proposal, we aim to build upon our promising preliminary results, and gain deeper insights into the cell biology of the pacDNA with respect to cell uptake mechanism, intracellular trafficking, KRAS depletion and subsequent cell signaling, and demonstrate efficacy in KRAS-dependent non-small cell lung cancer cell lines and 3D models. In addition, we will study the primary pharmacology and antitumor activity of pacDNA in advanced preclinical lung cancer models including an orthotopic tumor model, a patient derived tumor model, and a syngeneic genetically engineered mouse model (GEMM), and perform initial in vivo safety and tolerability studies. The outcome of this project will be a safe and potent anti-KRAS agent that can be readily translated into clinical studies for non-small cell lung cancer and potentially additional cancer classes.