Overcoming Evasion from Sorafenib in HCC

索拉非尼是第一个被证明有效的治疗肝癌的全身性药物。 然而，由于肝细胞癌迅速进化以避开索拉非尼的影响，因此肝细胞癌患者的生存期仅延长了约2个月。尽管索拉非尼的抗肿瘤作用最初归因于抑制RAF/IVIEK/ERK和血管内皮生长因子(VEGF)受体通路，但最近的临床试验对这一假设提出了挑战，显示出更有效和/或更有选择性的MEK和VEGF抑制剂的结果不一致。这些药物的有限疗效强调了有必要 了解氟氯烃如何逃避索拉非尼治疗。我们发现，在索拉非尼处理后存活的肝癌细胞含有L激活的EK和ERK，ERK的激活介导了其在治疗后的存活。在目标1中，我们将研究MEK/ERK激活的作用--在我们测试的所有肝癌细胞系中都是一致的--作为细胞自主逃避索拉非尼的机制。对血管内皮生长因子阻断的回避也强调了测试索拉非尼是否导致治疗后促进肝癌生长的肿瘤间质变化(例如，缺氧)的必要性。我们发现低氧水平，间质- 索拉非尼治疗后，肝细胞癌组织中衍生因子1a(SDFIa)表达增加，Gr-1骨髓衍生细胞(BMDCs)数量增加，纤维化程度增加。我们将在AIM 2中研究肝癌中索拉非尼治疗逃避的肿瘤间质机制，并剖析SDFIa上调、BMDC募集和肝癌中肿瘤纤维化之间的因果联系。最后，我们的初步数据表明，与单独使用索拉非尼相比，在索拉非尼中添加MEK/ERK或SDF1a/CXCR4抑制剂可以显著延缓肝癌的生长。在目标3中，我们将评估联合药理后的肿瘤反应和毒性。 MEK或CXCR4抑制剂与索拉非尼在(同基因和自发性)免疫活性小鼠原位肝癌模型中的联合应用。该项目的目标将在与多学科PPG团队的密切合作下实现。

Sorafenib is the first systemic tlierapy with proven efficacy against liepatoceilular carcinoma (HCC). However, since HCCs evolve rapidly to circumvent sorafenib's effects, survival in HCC patients is prolonged only about 2 months. Although the anti-tumor effect of sorafenib was initially attributed to inhibition of RAF/IVIEK/ERK and vascular endothelial growth factor (VEGF) receptor pathways, recent clinical trials have challenged this hypothesis by showing inconsistent results with even more potent and/or selective MEK and VEGF inhibitors. The limited efficacy of these agents emphasizes the need to understand how HCCs evade sorafenib treatment. We show that HCC cells that survive sorafenib treatment harbor activated l\/!EK and ERK, and that ERK activation mediates their viability after treatment. In Aim 1 we will investigate the role of MEK/ERK activation-consistently seen in all the HCC cell lines we have tested-as a cell autonomous mechanism of evasion from sorafenib. The evasion from VEGF blockade also emphasizes the need to test whether sorafenib induces changes in tumor stroma (e.g., hypoxia) that facilitate HCC growth after treatment. We found that hypoxia levels, stromal- derived factor 1a (SDFIa) expression, Gr-1+ bone marrow-derived cells (BMDCs) number and fibrosis are all increased after sorafenib treatment in HCC. We will examine tumor stromal mechanisms of evasion from sorafenib treatment in HCC, and dissect the causal links between SDFIa upregulation, BMDC recruitment and tumor fibrosis in HCC in Aim 2. Finally, our preliminary data suggest that adding MEK/ERK or SDF1a/CXCR4 inhibitors to sorafenib significantly delays HCC growth compared to sorafenib alone. In Aim 3, we will evaluate tumor response and toxicity after combining pharmacologic inhibitors of MEK or CXCR4 with sorafenib in (syngeneic and spontaneous) orthotopic HCC models in immunocompetent mice. The goals of this project will be achieved in close collaboration with the multidisciplinary PPG team.