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New therapeutic opportunities from mining polypharmacology mechanisms of ceritinib in ALK-negative non-small cell lung cancer

挖掘色瑞替尼治疗 ALK 阴性非小细胞肺癌的多药理学机制带来新的治疗机会

基本信息

批准号：
9354424
负责人：
BRENT KUENZI
金额：
$ 3.43万
依托单位：
UNIVERSITY OF SOUTH FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-19 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9354424
关键词：
Award Bioinformatics Biological Assay Biology Cancer Patient Cancer cell line Cell Survival Chemicals Chimeric Proteins Clinical Combined Modality Therapy Data Set Drug Targeting Drug effect disorder Drug usage FDA approved Gene Silencing Generations Genes Genetic Genetic Transcription Genomics IGF1R gene Immunoblotting Immunofluorescence Immunologic Immunohistochemistry Immunoprecipitation In Vitro Institutes Institution Iodine KRAS2 gene Knowledge Lead Letters Malignant Neoplasms Malignant neoplasm of lung Measures Mining Molecular Molecular Biology Techniques Mutation Non-Small-Cell Lung Carcinoma Oncogenes Oncogenic PTK2 gene Paclitaxel Pathway interactions Patients Pharmaceutical Preparations Pharmacology Phenotype Phosphotransferases Preclinical Drug Evaluation Proteins Proteomics RHOA gene Regulation Research Research Personnel Resistance Role Saint Jude Children&apos s Research Hospital Scientist Signal Transduction System Systems Biology Technology Testing Training Tubulin Tumor Volume Work Xenograft Model actionable mutation anaplastic lymphoma kinase anticancer activity anticancer research base biomarker development cancer cell career clinical development crizotinib design drug candidate effective therapy experimental study in vivo inhibitor/antagonist interest killings kinase inhibitor knock-down medical specialties mutant nano-string novel novel drug combination novel strategies novel therapeutic intervention novel therapeutics overexpression patient stratification patient subsets phosphoproteomics pre-doctoral prevent programs resistance gene synergism

项目摘要

Project Summary While there have been advances in targeting actionable oncogenes such as ALK fusion proteins, the majority of non-small cell lung cancer patients feature either difficult to target mutations, e.g. KRAS, or lack known oncogenic drivers. These patients do not derive much benefit from currently approved therapies. Therefore, in order to find effective treatments for these patients, novel strategies need to be implemented to find therapies that are able to kill lung cancer cells and can be rapidly implemented clinically. Many targeted drugs show potent anticancer activity in subsets of NSCLC, which is often unrelated to inhibition of the cognate targets of these drugs. These beneficial off-targets can be exploited to identify novel drug repurposing opportunities that allow for the treatment of these difficult to treat cancers. Detailed drug profiling is best done using unbiased chemical and systems biology approaches. Chemical proteomic experiments investigate direct drug-protein interactomes giving a number of possible candidate targets. These interactomes can be integrated with global signaling changes measured by phosphoproteomics to give a comprehensive view of the mechanism of action of a drug. Ceritinib is an FDA-approved ALK/IGF1R inhibitor for the treatment of ALK positive non-small cell lung cancer (NSCLC) and we observed that ceritinib has unexpected activity in KRAS mutant NSCLC. A focused chemical proteomic profiling of ceritinib has identified a number of novel targets of ceritinib including FAK1 and RSK1/2. Preliminary studies into ceritinib’s mechanism of action have shown alterations in the cross talk signaling between the KRAS and RHOA pathways. However, the functional relevance and exact molecular mechanisms of such regulation remain unclear. Finally, based on this mechanism we designed a novel drug combination strategy combining ceritinib with the FDA-approved tubulin inhibitor, paclitaxel. We will test the hypothesis that the molecular determinants following inhibition of FAK1 and RSK1/2 by ceritinib carry predictive ability for ceritinib and paclitaxel combination efficacy by achieving the following aims. Aim 2.1: To evaluate the role of YB1 in the observed synergy between ceritinib and paclitaxel. Aim 2.2: To investigate the role of GEF-H1 in ceritinib’s mechanism of action. Aim 2.3: To characterize both ceritinib monotherapy and paclitaxel combination therapy in KRAS-mutant NSCLC PDX models. We will then have a greater understanding of the relevant downstream molecular determinants of ceritinib’s mechanism of action and of the observed synergy with paclitaxel. This will ultimately lead to predictive capabilities for ceritinib sensitivity and further clinical development of ceritinib to treat patients whom will benefit.

项目摘要虽然在靶向可作用的癌基因如ALK融合蛋白方面取得了进展，但大多数研究都是在靶向可作用的癌基因方面取得的。的非小细胞肺癌患者的特征是难以靶向突变，例如KRAS，或缺乏已知的致癌驱动因子这些患者从目前批准的治疗中获益不大。因此在为了给这些患者找到有效的治疗方法，需要实施新的策略来寻找治疗方法能够杀死肺癌细胞，并且可以在临床上快速实施。许多靶向药物显示在NSCLC亚群中具有强效抗癌活性，通常与抑制这些药物。可以利用这些有益的脱靶来识别新的药物再利用机会，让这些难以治疗的癌症得到治疗。详细的药物分析最好使用无偏见的化学和系统生物学方法进行。化学蛋白质组学实验研究了直接的药物-蛋白质相互作用组，目标的这些相互作用组可以与磷酸化蛋白质组学测量的全球信号变化整合全面了解药物的作用机制。Ceritinib是FDA批准的ALK/IGF 1 R 治疗ALK阳性非小细胞肺癌（NSCLC）的抑制剂，我们观察到塞瑞替尼在KRAS突变型NSCLC中具有意想不到的活性。塞瑞替尼的集中化学蛋白质组学分析确定了塞瑞替尼的许多新靶点，包括FAK 1和RSK 1/2。塞瑞替尼的初步研究作用机制已经显示出KRAS和RHOA之间的串扰信号传导的改变途径。然而，这种调节的功能相关性和确切的分子机制仍然存在不清楚最后，基于这一机制，我们设计了一种新的联合塞瑞替尼的药物组合策略用的是FDA批准的微管蛋白抑制剂紫杉醇我们将检验塞瑞替尼抑制FAK 1和RSK 1/2后的分子决定因素通过实现以下目标，具有塞瑞替尼和紫杉醇联合治疗疗效的预测能力。目标2.1：评价YB 1在塞瑞替尼和紫杉醇之间观察到的协同作用中的作用。目标2.2：调查 GEF-H1在塞瑞替尼作用机制中的作用。目的2.3：描述塞瑞替尼单药治疗和紫杉醇联合治疗KRAS突变型NSCLC PDX模型。我们将有一个更大的了解塞瑞替尼作用机制的相关下游分子决定因素，观察到与紫杉醇的协同作用。这将最终导致塞瑞替尼敏感性的预测能力，塞瑞替尼的进一步临床开发，以治疗将受益的患者。