Improving Sorafenib; a multi-targeted kinase inhibitor used for the treatment of hepatocellular carcinoma by mechanistically dissecting out its underlying targets and anti-targets

改进索拉非尼；

基本信息

批准号：
9314220
负责人：
Jia Yu
金额：
$ 4.12万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
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：
2016-07-08 至 2019-07-07
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9314220
关键词：
Adverse effects Animal Model Animals BAY 54-9085 Biochemical Biochemical Genetics Biological Assay Cancer Patient Cell Cycle Regulation Cell Line Cell Survival Cells Clinical Trials Coculture Techniques Code Collaborations Data Diagnosis Disease Drosophila genus Drug Targeting Drug effect disorder Effectiveness Employee Strikes Equilibrium Gene Expression Genetic Genetic Models Genetic Models for Cancer Growth Hep3B Hepatic Stellate Cell Impairment Incidence Induction of Apoptosis KDR gene Lead Libraries Life Liver Liver diseases Long-Term Effects Longevity Malignant Epithelial Cell Malignant Neoplasms Malignant neoplasm of liver Modeling Mutation Operative Surgical Procedures PDGFRB gene Pancreas Pathway Analysis Pathway interactions Patients Pharmaceutical Preparations Pharmacology Phosphotransferases Phthalimides Placebos Primary carcinoma of the liver cells Probability Proteins Radiation Raf Kinase Inhibitor Receptor Protein-Tyrosine Kinases Resistance Reverse Transcriptase Polymerase Chain Reaction Role Sampling Signal Pathway Structure-Activity Relationship TP53 gene Telomerase Testing Therapeutic Therapeutic Index Time Toxic effect WNT Signaling Pathway analog base chemical genetics chromatin remodeling cost cytotoxic drug efficacy extracellular fly genetic approach hepatocellular carcinoma cell line improved in vivo inhibitor/antagonist insight kinase inhibitor mortality novel promoter response small molecule stable cell line standard of care targeted treatment tumor

项目摘要

PROJECT SUMMARY/ABSTRACT Liver cancer is one of the most common and lethal cancers; hundreds of thousands of new cases occur yearly with only a 20% chance of survival one year past diagnosis. Furthermore, the mortality rate of liver cancer is increasing beyond most other cancers. Hepatocellular carcinoma (HCC) makes up to 70-85% of all cases of liver cancer, and currently only the multi-targeted kinase inhibitor Sorafenib is approved as therapy outside of surgery and radiation. Sorafenib was first approved in 2007, and since this time all subsequent approaches have thus far failed to improve upon an average 2.8 month extension in overall survival for liver cancer patients. A significant challenge in improving upon Sorafenib is that the mechanism of this drug, in particular the functional basis for efficacy and toxicity, remains poorly understood in HCC. Although originally developed as a RAF-kinase inhibitor, it is unlikely that RAF inhibitory activity is responsible for patient responses to Sorafenib. VEGFR has been suggested as an important target, yet other more potent VEGFR inhibitors have failed to extend life in comparison with Sorafenib. Due to the multi-kinase activity of Sorafenib, I hypothesize Sorafenib is modulating both undesirable anti-targets as well as desirable targets. I furthermore posit that it is the balance between the targets and anti-target activities of Sorafenib that largely determines the therapeutic index of this drug. Here, I propose to evaluate a focused library of Sorafenib analogs (Sorafelogs) to uncover structure-activity relationships (SAR) that will be used to identify functional targets and anti-targets of Sorafenib. We have already identified striking SAR with preliminary compounds in the context of HCC cell line models, and are using cross-comparison of these structurally related compounds to uncover the mechanistic basis for growth inhibition and the induction of apoptosis by Sorafenib. Putative physical targets will be validated using biochemical and genetic approaches. Furthermore, we have identified a Sorafelog, which we term AD80, which is 10 to 100-fold more cytotoxic on HCC cell lines than Sorafenib. However, in whole animals, this compound is well-tolerated suggesting limited side-effects. We will explore both Sorafenib and AD80’s targets and anti-targets using pathway analysis on cell line models, and a whole-body fly genetic model of HCC. These findings should lead to an optimized version of Sorafenib that would inhibit drivers (ie. targets), but avoid suppressors (anti-targets). These studies will provide a greater mechanistic understanding of viable therapeutic options for this heterogeneous disease, and furthermore will provide compounds that ideally reduce toxicity and increase efficacy in HCC. This will also help to better select patients with the highest probability of responding to Sorafelogs, and decrease the costs impaired by liver cancer.

项目概要/摘要肝癌是最常见和致命的癌症之一，每年都会发生数十万新病例。诊断后一年的生存率仅为 20% 此外，肝癌的死亡率为肝细胞癌 (HCC) 占所有肝癌病例的 70-85%，其发病率不断上升，超过了大多数其他癌症。癌症，目前只有多靶点激酶抑制剂索拉非尼被批准作为手术外的治疗方法索拉非尼于 2007 年首次获得批准，从那时起，所有后续方法均已获得批准。肝癌患者的总生存期平均延长了 2.8 个月，但远未能改善。改进索拉非尼的重大挑战是该药物的作用机制，特别是功能性尽管最初是作为 RAF 激酶开发的，但其功效和毒性的基础仍然知之甚少。抑制剂，RAF 抑制活性不太可能导致患者对索拉非尼产生反应。已被建议作为一个重要靶点，但其他更有效的 VEGFR 抑制剂未能延长患者的生命与索拉非尼的比较由于索拉非尼的多激酶活性，我勇敢地认为索拉非尼具有调节作用。我进一步认为，这是不受欢迎的反目标和理想目标之间的平衡。索拉非尼的靶点和抗靶点活性在很大程度上决定了该药物的治疗指数。建议评估索拉非尼类似物（Sorafelogs）的重点库以揭示结构-活性关系（SAR）将用于识别索拉非尼的功能靶点和反靶点。在 HCC 细胞系模型中使用初步化合物来提高 SAR，并使用交叉比较这些结构相关的化合物揭示了生长抑制和诱导的机制基础索拉非尼对细胞凋亡的影响将通过生化和遗传学方法进行验证。此外，我们还发现了一种 Sorafelog，我们称之为 AD80，其细胞毒性比 AD80 高 10 至 100 倍。 HCC 细胞系优于索拉非尼，但在整个动物中，该化合物的耐受性良好，表明其耐受性有限。我们将利用细胞通路分析来探索索拉非尼和 AD80 的靶点和反靶点。这些发现应该会导致 HCC 的优化版本。索拉非尼会抑制驱动因素（即目标），但避免抑制因素（反目标）。对这种异质性疾病的可行治疗选择有更深入的机制理解，以及此外，还将提供能够理想地降低毒性并提高 HCC 疗效的化合物。更好地选择对索拉菲洛有最高反应可能性的患者，并降低受损成本由肝癌引起。