Inhibiting oncogenic KRAS for cancer therapy

抑制致癌 KRAS 用于癌症治疗

• 批准号: 8637741
• 负责人: GARTH POWIS
• 金额: $ 38.03万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8637741
• 关键词: Amino Acid Substitution; Automobile Driving; Binding; CNKSR1 gene; Cancer Cell Growth; Cancer Patient; Cell Line; Cell Proliferation; Cell Survival; Cells; Clinical Trials; Codon Nucleotides; Computer Simulation; Custom; Data; Diagnosis; Drug Targeting; Grant; Human; Individual; KRAS2 gene; Knowledge; Lead; Libraries; Malignant Neoplasms; Microscopy; Modeling; Molecular; Mutation; Non-Small-Cell Lung Carcinoma; Oncogenes; Oncogenic; Pathway interactions; Patients; Pharmaceutical Preparations; Play; Proteins; Proteomics; Regulation; Role; Signal Pathway; Signal Transduction; Site; Small Interfering RNA; Techniques; Transducers; Work; X-Ray Crystallography; base; cancer therapy; cell growth; cellular engineering; effective therapy; improved; inhibitor/antagonist; mutant; novel; novel therapeutic intervention; oncogene addiction; response; small molecule; therapy development; therapy resistant; tumor

DESCRIPTION (provided by applicant): The RAS oncogene is the most elusive cancer therapy target yet identified. Mutant KRAS (mut-KRAS) is the predominant oncogenic form of RAS, and is present in 17-25% of all human cancers where it plays a critical role in driving cancer cell growth and resistance to therapy where it plays a critical role in driving cancer cell growth and resistance to therapy. Its effects are so powerful that it overrides the beneficial effects of many of the new molecularly targeted signaling agents in use for cancer today. Despite numerous attempts over the last two decades there is still no effective therapy for mut-KRAS. KRAS mutations are limited to a few sites, primarily codons 12 and 13, where different base transversions and transitions lead to different amino acid substitutions which vary in different tumor types. Understanding the signaling mechanisms activated by the different forms of mut-KRAS and finding agents to inhibit mut-KRAS signaling is arguably the most important unmet needs in cancer therapy today. New findings offer the potential of developing therapies that selectively inhibit mut-KRAS. The hypothesis upon which the studies are based is that: "Different forms of mut-KRAS activate different downstream signaling pathways regulating cancer cell growth and survival, leading to differences in patient response to therapy. Knowing which pathways are activated will allow selective inhibition of signaling by the different forms of mut-KRAS leading to improved therapy for mut-KRAS tumors. New evidence we present shows that targeting proteins of the mut-KRAS signaling nanocluster with small molecules can lead to selective inhibition of mut-KRAS but not wt-KRAS signaling and cell growth. Understanding how these nanocluster proteins work in regulating mut- and wt-KRAS activity will provide a window of opportunity for new therapeutic approaches for selective inhibition of mut-KRAS ". The overall objectives of our study are to gain a greater understanding of the structural and cellular mechanisms of signaling by different forms of mut-KRAS that could explain differences in patient response and resistance to therapy; and to investigate the mechanism of a new small molecule probe we have developed that binds to the RAS nanocluster to selectively inhibit mut-KRAS but not wt-KRAS signaling and cell growth. The Specific Aims are; 1) To investigate which of multiple KRAS downstream signaling pathways are activated by different mut-KRAS amino acid substitutions and the structural basis for the activation; 2) To investigate which signaling pathways are essential for mut-KRAS oncogene addiction and/or resistance to therapy; and 3) To investigate the regulation of mut-KRAS signaling by the RAS nanocluster and the mechanism of a small molecule nanocluster inhibitor that selectively inhibits mut-KRAS but not wt-KRAS cell proliferation.

描述(由申请人提供)：RAS癌基因是迄今确定的最难以捉摸的癌症治疗靶点。突变的KRAS(mut-KRAS)是RAS的主要致癌形式，存在于17-25%的人类癌症中，在推动癌细胞生长和抵抗治疗方面发挥关键作用，在推动癌细胞生长和抵抗治疗方面发挥关键作用。它的作用是如此强大，以至于它超过了今天用于癌症的许多新的分子靶向信号剂的有益效果。尽管在过去20年中进行了多次尝试，但仍然没有有效的治疗MUT-KRAS的方法。KRAS突变仅限于几个位点，主要是密码子12和13，不同的碱基颠倒和转换导致不同的氨基酸替换，这在不同的肿瘤类型中是不同的。了解不同形式的MUT-KRAS激活的信号机制，并找到抑制MUT-KRAS信号的药物，可以说是当今癌症治疗中最重要的未得到满足的需求。新的发现提供了开发选择性抑制MUT-KRAS的治疗方法的潜力。这些研究所基于的假设是：“不同形式的MUT-KRAS激活不同的下游信号通路，调节癌细胞的生长和存活，导致患者对治疗的反应不同。知道哪些通路被激活，将允许选择性地抑制不同形式的信号 MUT-KRAS导致对MUT-KRAS肿瘤治疗的改进。我们提出的新证据表明，以小分子靶向mut-KRAS信号纳米簇的蛋白可以选择性地抑制mut-KRAS信号，但不能抑制wt-KRAS信号和细胞生长。了解这些纳米簇蛋白如何调节MUT-和WT-KRAS活性，将为选择性抑制MUT-KRAS的新治疗方法提供机会之窗“。我们研究的总体目标是更好地了解不同形式的MUT-KRAS信号的结构和细胞机制，这可以解释患者对治疗的反应和耐药性的差异；并研究我们开发的一种新的小分子探针的机制，该探针与RAS纳米簇结合，选择性地抑制MUT-KRAS信号和细胞生长，但不抑制WT-KRAS信号和细胞生长。其具体目的是：1)研究MUT-KRAS下游信号通路中哪些被不同的MUT-KRAS氨基酸替换激活以及激活的结构基础；2)研究哪些信号通路是MUT-KRAS癌基因成瘾和/或治疗耐药所必需的；以及3)研究RAS纳米簇对MUT-KRAS信号的调节以及选择性抑制MUT-KRAS而不是WT-KRAS细胞增殖的小分子纳米簇抑制剂的机制。