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

项目总结/摘要 肝癌是最常见和致命的癌症之一，每年有数十万新病例发生 确诊后一年的存活率只有20%此外，肝癌的死亡率是 超过大多数其他癌症。肝细胞癌（HCC）占所有肝脏病例的70- 85 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 和辐射。索拉非尼于2007年首次获得批准，从那时起，所有后续方法都因此 Far未能改善肝癌患者平均2.8个月的总生存期延长。一 改进索拉非尼的一个重大挑战是，这种药物的机制，特别是功能性 疗效和毒性的基础，在HCC中仍然知之甚少。虽然最初是作为RAF激酶开发的， 因此，RAF抑制活性不太可能导致患者对索拉非尼的反应。VEGFR具有 被认为是一个重要的目标，但其他更有效的VEGFR抑制剂未能延长生命， 与索拉非尼比较由于索拉非尼的多激酶活性，我假设索拉非尼是调节 既有不希望的反靶标，也有希望的靶标。我进一步强调，这是一种平衡， 索拉非尼的靶点和抗靶点活性在很大程度上决定了这种药物的治疗指数。这里我 我建议评估索拉非尼类似物（索拉菲洛）的集中文库，以揭示结构-活性关系 (SAR)其将用于鉴定索拉非尼的功能靶标和抗靶标。我们已经确定 在HCC细胞系模型的背景下，使用初步化合物进行惊人的SAR，并使用交叉比较 这些结构相关的化合物，以揭示生长抑制和诱导的机制基础， 索拉非尼诱导的凋亡。将使用生物化学和遗传学方法验证假定的物理靶点。 此外，我们已经鉴定了一种Sorafelog，我们称之为AD 80，它对人结肠癌细胞的细胞毒性是人结肠癌细胞的10至100倍。 HCC细胞系比索拉非尼。然而，在整个动物中，该化合物耐受性良好，这表明其耐受性有限。 副作用我们将利用细胞信号通路分析来探索索拉非尼和AD 80的靶点和反靶点。 系模型和HCC的全身蝇遗传模型。这些发现应该导致一个优化版本的 索拉非尼，将抑制驱动程序（即。目标），但避免抑制剂（反目标）。这些研究将提供 对这种异质性疾病的可行治疗方案有更深入的机制理解， 还将提供理想地降低HCC中的毒性并增加其功效的化合物。这也将有助于 更好地选择对索拉菲洛格反应概率最高的患者，并降低受损成本 被肝癌感染。

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.