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癌基因是尚未确定的最难以捉摸的癌症治疗靶标。突变的KRAS（MUT-KRAS）是RAS的主要致癌形式，在所有人类癌症中，有17-25％的人在驱动癌细胞生长和对治疗的抵抗力中起着至关重要的作用，在该治疗中它在驱动癌细胞生长和对治疗的耐药性中起着至关重要的作用。它的作用是如此强大，以至于它覆盖了当今用于癌症的许多新分子靶向信号剂的有益作用。尽管在过去的二十年中进行了许多尝试，但对于Mut-Kras仍没有有效的疗法。 KRAS突变仅限于几个位点，主要是密码子12和13，其中不同的碱基横向和过渡会导致不同的氨基酸取代，这些氨基酸取代在不同的肿瘤类型中变化。了解不同形式的Mut-Kras激活的信号传导机制，并发现抑制Mut-Kras信号传导的药物可以说是当今癌症治疗中最重要的未满足需求。新发现提供了开发有选择性抑制Mut-Kras的疗法的潜力。研究所基于的假设是：“不同形式的mut-kras激活了调节癌细胞生长和存活的不同下游信号通路，从而导致患者对治疗的反应差异。知道哪些途径被激活将允许通过不同形式的不同形式的信号传导。 MUT-KRA会改善对MUT-KRAS肿瘤的治疗。我们提供的新证据表明，用小分子靶向MUT-KRAS信号转导纳米簇的蛋白质会导致对MUT-KRAS的选择性抑制，而不是WT-KRAS信号传导和细胞生长。了解这些纳米簇蛋白如何在调节MUT和WT-KRAS活性方面起作用，将为新的治疗方法提供选择性的选择性抑制MUT-KRAS的方法。我们研究的总体目标是获得对MUT-KRAS的不同形式的结构和细胞机制的更深入的理解，从而可以通过不同形式的MOUREC机制来解释较小的患者响应和差异的差异，以解释差异的差异，以解释对差异的差异和差异的差异。我们已经开发出与RAS纳米簇结合，可抑制MUT-KRAS，但不是WT-KRAS信号传导和细胞的生长。进行治疗； 3）调查RAS纳米簇对MUT-KRAS信号的调节，以及一个小分子纳米簇抑制剂的机制，该抑制剂有选择地抑制MUT-KRAS，但不抑制WT-KRAS细胞的增殖。