Stat3 and anti-VEGF therapy in cancer

描述（由申请人提供）：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、对常规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VEGF治疗仍然是一个挑战，部分原因是许多转化事件，包括致癌激酶的激活和肿瘤抑制基因的失活，都会诱导VEGF的表达。最近，我们发现Stat3是VEGF启动子的一种新的转录调节因子。值得注意的是，Stat3在多种癌症中以50-90%的频率被组成性激活，许多已知的vegf诱导剂通过Stat3发出信号。此外，肿瘤抑制因子PTEN和p53是VEGF基因表达的重要负调控因子。PTEN最近被证明可以抑制Stat3活性，这表明PTEN活性的丧失会增加Stat3介导的VEGF上调。此外，我们的初步研究表明Stat3抑制p53的表达，表明Stat3在抑制p53对VEGF下调的作用中起作用。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的必要条件。在发现Stat3/VEGF连接之前，HIF-1是唯一已知的VEGF转录因子，其在介导致癌激酶和p53/PTEN肿瘤抑制因子诱导VEGF中的重要作用已被证实。这些发现使我们假设Stat3不仅是VEGF启动子的直接调节剂，也是许多其他VEGF诱导剂的效应器和/或调节剂。我们的研究结果表明，Stat3与VEGF启动子的结合对于Src酪氨酸激酶诱导的VEGF上调是必需的。在这里，我们提出确定Stat3是否也将来自Stat3上游的其他VEGF诱导剂的信号直接传递给VEGF启动子。我们还将评估Stat3控制HIF-1 α表达的分子机制。最后，由于Stat3阻断抑制VEGF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/血管塌陷如何影响肿瘤细胞凋亡/肿瘤消退，反之亦然。总的来说，这些研究可能会导致开发出更有效的用于癌症治疗的VEGF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.