Stat3 and anti-VEGF therapy in cancer

描述(申请人提供)：血管内皮生长因子(VEGF)对肿瘤血管生成和肿瘤免疫抑制至关重要。它在肿瘤中的高表达与肿瘤转移增加、对传统治疗药物的耐药性和癌症患者的低生存率有关。然而，有效的抗血管内皮生长因子治疗仍然是一个挑战，部分原因是许多转化事件，包括癌基因激酶的激活和肿瘤抑制基因的失活，诱导了血管内皮生长因子的表达。最近，我们发现STAT3是一种新的血管内皮生长因子启动子转录调控因子。值得注意的是，STAT3在不同的癌症中被结构性激活，频率为50%-90%，许多已知的血管内皮生长因子诱导因子通过STAT3发出信号。此外，抑癌基因PTEN和P53是血管内皮生长因子基因表达的重要负调控因子。最近发现PTEN可以抑制STAT3的活性，提示PTEN活性的丧失会增加STAT3介导的血管内皮生长因子的上调。此外，我们的初步研究表明，STAT3抑制了P53的表达，这表明STAT3在抵消P53对血管内皮生长因子下调的影响中发挥了作用。此外，我们的初步结果表明，STAT3信号是诱导缺氧诱导因子1(HIF-1)α所必需的。在发现STAT3/VEGF连接之前，HIF-1是已知的唯一一种VEGF转录因子，它在癌基因激酶和P53/PTEN肿瘤抑制因子诱导的血管内皮细胞生长中发挥重要作用。这些发现使我们推测，STAT3不仅是血管内皮生长因子启动子的直接调节者，也是许多其他血管内皮生长因子诱导物的效应者和/或调节者。我们的结果表明，STAT3与血管内皮生长因子启动子的结合是Src酪氨酸激酶诱导血管内皮生长因子上调所必需的。在这里，我们建议确定STAT3是否也将信号从STAT3上游的其他血管内皮生长因子诱导剂直接传递到血管内皮生长因子启动子。我们还将评估STAT3控制HIF-1α表达的分子机制(S)。最后，由于STAT3阻断可抑制血管内皮生长因子的表达和血管生成，同时下调几个关键的抗凋亡基因，并诱导肿瘤细胞凋亡和肿瘤消退，我们将有一个独特的机会来评估内皮细胞死亡/血管崩溃如何影响肿瘤细胞的凋亡/肿瘤消退，反之亦然。总而言之，这些研究可能会导致开发出更有效的癌症治疗用血管内皮生长因子抑制剂。

DESCRIPTION (provided by applicant): Vascular endothelial growth factor (VEGF) is critical for tumor angiogenesis and tumor immune suppression. Its elevated expression in tumors has been correlated with increased metastasis, resistance to conventional therapeutic agents and poor survival rates for cancer patients. However, effective anti-VEGF therapy remains a challenge in part because numerous transforming events, including activation of oncogenic kinases and inactivation of tumor suppressor genes, induce VEGF expression. Recently, we have identified Stat3 as a novel transcriptional regulator of the VEGF promoter. Significantly, Stat3 is constitutively-activated with 50-90% frequency in diverse cancers and many known VEGF-inducers signal through Stat3. Moreover, the tumor suppressors, PTEN and p53, are important negative regulators of VEGF gene expression. PTEN has recently been shown to inhibit Stat3 activity, suggesting that loss of PTEN activity would increase Stat3-mediated VEGF up-regulation. Furthermore, our preliminary studies have shown that Stat3 inhibits p53 expression, indicating a role of Stat3 in negating p53 effects on VEGF down-regulation. In addition, our preliminary results show that Stat3 signaling is required for induction of hypoxia-inducing factor 1 (HIF-1) alpha. Prior to discovery the Stat3/VEGF connection, HIF-1 was the only known VEGF transcriptional factor and its important role in mediating VEGF induction by oncogenic kinases and the p53/PTEN tumor suppressors has been established. These findings led us to hypothesize that Stat3 is not only a direct regulator of the VEGF promoter but also an effector and/or regulator of numerous other VEGF inducers. Our results demonstrate that binding of Stat3 to the VEGF promoter is obligatory for Src tyrosine kinase-induced VEGF up-regulation. Here we propose to determine whether Stat3 also transmits signals from other VEGF inducers up-stream of Stat3 directly to the VEGF promoter. We will also assess the molecular mechanism(s) by which Stat3 controls HIF-1 alpha expression. Finally, because Stat3 blockade inhibits VEGF expression and angiogenesis while at the same time down-regulates several key antiapoptotic genes and induces tumor cell apoptosis and tumor regression, we will have a unique opportunity to assess how endothelial cell death/vessel collapse affects tumor cell apoptosis/tumor regression and vice versa. Collectively, these studies may lead to development of more potent VEGF inhibitors for cancer therapy.