Overcoming Evasion from Sorafenib in HCC

索拉非尼是第一个被证实对肝细胞癌（HCC）有效的全身性化疗药物。 然而，由于HCC迅速演变以规避索拉非尼的作用，HCC患者的存活仅延长约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）受体途径，但最近的临床试验通过显示与更有效和/或选择性MEK和VEGF抑制剂不一致的结果来挑战这一假设。这些药剂的有限功效强调了需要 了解HCC如何逃避索拉非尼治疗。我们发现，索拉非尼治疗后存活的肝癌细胞具有激活的l/！EK和ERK，并且ERK活化介导它们在处理后的活力。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HCC细胞系中一致观察到-作为逃避索拉非尼的细胞自主机制。对VEGF阻断的逃避也强调了测试索拉非尼是否诱导肿瘤基质变化（例如，缺氧），其在治疗后促进HCC生长。我们发现缺氧程度，基质- 肝癌患者接受索拉非尼治疗后，Gr-1+骨髓衍生细胞（BMDC）数量和纤维化程度均增加。我们将在Aim 2中研究HCC中逃避索拉非尼治疗的肿瘤基质机制，并剖析HCC中SDFIa上调、BMDC募集和肿瘤纤维化之间的因果关系。最后，我们的初步数据表明，与单独使用索拉非尼相比，在索拉非尼中加入MEK/ERK或SDF 1a/CXCR 4抑制剂可显著延迟HCC的生长。在目标3中，我们将评估联合药物治疗后的肿瘤反应和毒性， MEK或CXCR 4抑制剂与索拉非尼在免疫活性小鼠（同基因和自发）原位HCC模型中的作用。该项目的目标将与多学科PPG团队密切合作实现。

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.