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

项目摘要/摘要 突变形式的KRAS是人类肿瘤的关键驱动因素，但对治疗干预仍然难以奏效 尽管经过了三十多年的研究。临床上直接或间接抑制KRAS功能的尝试 这两种方法的结果都不令人满意。开发小分子KRAS抑制剂的难度增加 针对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，这使得它有可能耗尽传统药物难以处理的目标蛋白质。我们 已经开发出一种名为pacDNA的新型核酸疗法，它大大增强了 核酸药物通过提高体内稳定性、加速细胞摄取和改善其抗肿瘤活性 血浆药代动力学和肿瘤蓄积，允许使用比 传统的方法。PacDNA还抑制了几乎所有与传统核技术相关的副作用。 通过减少不必要的核酸-蛋白质相互作用来酸化药物。在这项建议中，我们的目标是在我们的 有希望的初步结果，并获得更深入的洞察力的细胞生物学的PacDNA与细胞 摄取机制、细胞内转运、KRAS耗竭和随后的细胞信号转导，并证明 KRAS依赖的非小细胞肺癌细胞系和3D模型的疗效。此外，我们还将研究 PacDNA在晚期临床前肺癌模型中的初步药理和抗肿瘤活性 原位肿瘤模型、患者来源的肿瘤模型和同基因工程小鼠 模型(GEMM)，并进行初步的体内安全性和耐受性研究。这个项目的结果将是一个 安全有效的抗KRAS药物，易于转化为非小细胞肺的临床研究 癌症和潜在的额外癌症课程。

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.