Axl as a target for the therapy of pancreatic cancer

Axl 作为胰腺癌治疗靶点

• 批准号: 8431020
• 负责人: Rolf A Brekken
• 金额: $ 20.75万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-13 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8431020
• 关键词: Address; Adenocarcinoma Cell; Animal Model; Antibodies; Anticoagulants; Biology; Caring; Cell Adhesion Molecules; Cell Proliferation; Cell Survival; Cells; Clinical; Collaborations; Data; Development; Dimerization; Dose; Drug resistance; Extracellular Domain; Family; Foundations; Goals; Growth; Histocompatibility Testing; Human; In Vitro; Laboratories; Ligand Binding; Ligands; Malignant - descriptor; Malignant neoplasm of pancreas; Mitogen-Activated Protein Kinases; Modality; Modeling; Monoclonal Antibodies; Mus; Neoplasm Metastasis; Operative Surgical Procedures; Oral; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Phenotype; Phosphotransferases; Pilot Projects; Protein Tyrosine Kinase; Proteins; Receptor Activation; Receptor Inhibition; Receptor Protein-Tyrosine Kinases; Recruitment Activity; Regimen; Signal Pathway; Signal Transduction; Specificity; Stem cells; Stromal Cells; Stromal Neoplasm; Tertiary Protein Structure; Testing; Therapeutic; Therapeutic Agents; Treatment Efficacy; Tumor Angiogenesis; Tumor Burden; Tumor Cell Invasion; Tyrosine Kinase Inhibitor; Universities; Vitamin K; Warfarin; Xenograft Model; autocrine; axl receptor tyrosine kinase; carboxylate; chemotherapy; combat; drug sensitivity; efficacy evaluation; epithelial to mesenchymal transition; gamma-glutamyl carboxylase; gemcitabine; in vivo; in vivo Model; inhibitor/antagonist; innovation; insight; macrophage; malignant breast neoplasm; migration; neoplastic cell; novel therapeutics; pancreatic cancer cells; paracrine; public health relevance; receptor; receptor expression; research clinical testing; response; small molecule; standard of care; treatment strategy; tumor; tumor microenvironment; tumor progression

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.

描述（由申请人提供）：胰腺导管腺癌（PDAC）中受体酪氨酸激酶Axl的表达升高与转移增加和生存期缩短相关。 Axl 通过肿瘤细胞存活、增殖参与恶性进展， 耐药性、上皮间质转化和肿瘤基质激活，包括血管生成和肿瘤相关巨噬细胞招募。 Axl 由单一配体激活，即维生素 K 依赖性 γ-羧基谷氨酸 (GLA) 结构域蛋白 Gas6。异常激活可以通过非配体机制发生，包括相邻细胞上 Axl 胞外结构域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，但尚未评估在 PDAC 动物模型中靶向 Axl 的效果。我们的初步研究证明，胰腺癌细胞中的 Axl 抑制可减少 PI3K-Akt 和 MAP 激酶信号传导，并大大降低原位模型中的原发性和转移性负担。在本提案中，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 进展并增强对标准护理化疗的敏感性。我们将通过以下目标来解决这一假设：1）确定临床维生素K依赖性羧化酶抑制剂华法林抑制Gas6配体与Axl结合的治疗效果； 2) 表征新疗法直接抑制 Axl 信号转导的抗肿瘤作用。我们已经证明华法林可以降低 Axl 活性，其剂量远低于抗凝活性所需的剂量。我们发现华法林以 Axl 依赖性方式减轻胰腺癌原位模型中的肿瘤负荷并阻止转移。我们将扩大这些研究范围，包括评估华法林在 PDAC 本土模型中的疗效。我们将与 James Lorens 教授的实验室（卑尔根大学）合作，探索新型抑制性抗 Axl 单克隆抗体 10C9 和最近开发的口服小分子 Axl 受体酪氨酸激酶抑制剂 (BGB324) 的功效。 10C9和BGB324直接抑制Axl的治疗效果将在胰腺癌的相关体内模型中进行测试。我们的目标包括阻断 Gas6 依赖性自分泌/旁分泌和非配体 Axl 激活。我们的总体目标是证明 Axl 抑制是治疗胰腺癌的可行治疗策略，并确定 Axl 抑制是否与当前的治疗方式有效结合。