Axl as a target for the therapy of pancreatic cancer

描述(申请人提供)：受体酪氨酸激酶Axl在胰腺导管腺癌(PDAC)中的高表达与转移增加和生存期缩短有关。AXL通过肿瘤细胞存活、增殖、 耐药、上皮向间充质转化和肿瘤间质激活，包括血管生成和肿瘤相关巨噬细胞募集。AXL被一种单一的配体激活，即维生素K依赖的伽马羧谷氨酸(GLA)结构域蛋白Gas6。异常激活可以通过非配基机制发生，包括相邻细胞上Axl胞外区之间的同型相互作用，与其他受体酪氨酸激酶和细胞质酪氨酸激酶(例如，Src家族)的串扰。抑制Axl可阻断乳腺癌的转移活性并增强药物敏感性，但靶向Axl在PDAC动物模型中的作用尚未得到评估。我们的初步研究证明，抑制胰腺癌细胞中的Axl可以减少PI3K-Akt和MAP激酶信号转导，并显著降低原位模型中的原发和转移负担。在目前的提案中，我们将扩展这些研究，并评估三种不同策略在体内消除AxL活性的治疗效果。该提案的中心假设是，靶向AXL将阻止PDAC的进展，并增强对标准护理化疗的敏感性。我们将从以下几个方面探讨这一假说：1)确定临床应用维生素K依赖的羧基酶抑制剂华法林抑制AXL与Gas6配体结合的疗效；2)用新的治疗方法鉴定直接抑制AXL信号转导的抗肿瘤作用。我们已经证明，华法林在远低于抗凝活性所需的剂量时可以降低Axl的活性。我们发现，在胰腺癌原位模型中，华法林以AXL依赖的方式减轻肿瘤负担并阻止转移。我们将扩大这些研究，以包括对华法林在PDAC本土模型中的疗效的评估。我们将与卑尔根大学James Lorens教授的实验室合作，探索一种新的抑制性抗Axl单抗10C9和最近开发的口服小分子Axl受体酪氨酸激酶抑制剂(BGB324)的疗效。10C9和BGB324直接抑制Axl的治疗效果将在相关的胰腺癌体内模型中进行测试。我们的目标包括阻断依赖Gas6的自分泌/旁分泌和非配体Axl的激活。我们的总体目标是证明抑制AXL是治疗胰腺癌的一种可行的治疗策略，并确定抑制AXL是否与当前的治疗方式有效结合。

DESCRIPTION (provided by applicant): Elevated expression of the receptor tyrosine kinase Axl in pancreatic ductal adenocarcinoma (PDAC) is associated with increased metastasis and shorter survival. Axl participates in malignant progression via tumor cell survival, proliferation, drug resistance, epithelial-to-mesenchymal transition and tumor stromal activation including angiogenesis and tumor-associated macrophage recruitment. Axl is activated by a single ligand, the vitamin K-dependent gamma-carboxyglutamic (GLA) domain protein, Gas6. Aberrant activation can occur through non-ligand mechanisms including homotypic interaction between Axl extracellular domains on adjacent cells, crosstalk with other receptor tyrosine kinases and cytoplasmic tyrosine kinases (e.g., Src family). Inhibition of Axl blocks metastatic activity and enhances drug sensitivity in breast cancer, but the effect of targeting Axl in animal models of PDAC has not been evaluated. Our preliminary studies document that Axl inhibition in pancreatic cancer cells diminishes PI3K-Akt and MAP kinase signaling and strongly reduces primary and metastatic burden in orthotopic models. In the present proposal, we will expand on these studies and evaluate the therapeutic efficacy of three different strategies to abrogate Axl activity in vivo. The central hypothesis of the proposal is that targeting Axl will block PDAC progression and enhance sensitivity to standard-of-care chemotherapy. We will address this hypothesis with the following aims 1) to determine the therapeutic efficacy of inhibiting Gas6 ligand binding to Axl with the clinical vitamin K-dependent carboxylase inhibitor warfarin; 2) to characterize the anti-tumor effects of direct inhibition of Axl signal transduction with novel therapeutics. We have documented that warfarin can reduce Axl activity at doses much lower than those required for anticoagulant activity. We have found that warfarin reduces tumor burden and blocks metastasis in orthotopic models of pancreatic cancer in an Axl dependent manner. We will expand these studies to include evaluation of the efficacy of warfarin in autochthonous models of PDAC. In collaboration with Prof. James Lorens' laboratory (University of Bergen) we will explore the efficacy of a new inhibitory anti-Axl monoclonal antibody, 10C9 and a recently developed oral, small molecule Axl receptor tyrosine kinase inhibitor (BGB324). The therapeutic efficacy of direct Axl inhibition with 10C9 and BGB324 will be tested in relevant in vivo models of pancreatic cancer. Our aims encompass blockade of Gas6-dependent autocrine/paracrine and non-ligand Axl activation. Our overall goal is to document that inhibition of Axl is a viable therapeutic strategy for the treatment of pancreatic cancer and to determine if Axl inhibition combines effectively with current treatment modalities.