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.

项目摘要/摘要肝癌是最常见和致命的癌症之一。每年发生数十万个新案件过去一年的诊断机会只有20％的生存机会。此外，肝癌的死亡率是超越大多数其他癌症。肝细胞癌（HCC）最多占所有肝脏病例的70-85％癌症，目前只有多靶性激酶抑制剂索拉非尼被批准为手术以外的治疗和辐射。索拉非尼（Sorafenib）于2007年首次获得批准，此后所有随后的方法已经对于肝癌患者的总体存活率平均延长了2.8个月，因此无法改善。一个改善索拉非尼的重大挑战是该药物的机制，尤其是功能效率和毒性的基础在HCC中仍然很少了解。虽然最初是作为皇家空军基酶开发的抑制剂，RAF抑制活性不太可能导致患者对索拉非尼的反应。 VEGFR拥有被认为是一个重要的目标，但其他更多潜在的VEGFR抑制剂未能延长生命与索拉非尼进行比较。由于索拉非尼的多激酶活性，我假设索拉非尼正在调节两种不良的反目标和理想的目标。我进一步肯定这是索拉非尼的靶标和抗目标活性在很大程度上决定了该药物的治疗指数。在这里，我提议评估索拉非尼类似物（索拉替氏）的重点库，以发现结构活性关系（SAR）将用于识别索拉非尼的功能目标和抗目标。我们已经确定了在HCC细胞系模型的背景下，用初步化合物敲击SAR，并使用交叉比较这些与结构相关的化合物中的生长抑制和诱导的机械基础索拉非尼的凋亡。推定的物理靶标将使用生化和遗传方法验证。此外，我们已经确定了一个索拉氏菌，我们称其为AD80，在10至100倍的细胞毒性上 HCC细胞系比索拉非尼。但是，在整个动物中，这种化合物的耐受性良好表明有限副作用。我们将使用细胞上的途径分析探索索拉非尼和AD80的目标和反目标线模型和HCC的全身蝇遗传模型。这些发现应导致优化版本的索拉非尼会抑制驱动因素（即目标），但要避免补充剂（反靶标）。这些研究将提供对这种异质性疾病的可行治疗选择的更深入理解，以及此外，将提供理想地降低毒性并提高HCC效率的化合物。这也会有所帮助更好地选择对索拉氏菌反应的可能性最高的患者，并降低成本受损由肝癌。