Preclinical Testing of a Novel Therapy Targeting AXL in Advanced Kidney Cancer

针对晚期肾癌 AXL 的新疗法的临床前测试

• 批准号: 9889921
• 负责人: Erinn B. Rankin
• 金额: $ 48.33万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9889921
• 关键词: Affinity; Angiogenesis Inhibitors; Antibodies; Antimetastatic Agent; Binding; Biological; Biological Markers; Biological Products; Blood Vessels; Cancer Etiology; Cell Line; Cells; Cessation of life; Chimeric Proteins; Clear cell renal cell carcinoma; Clinic; Combined Modality Therapy; Data; Development; Disease; Disease Resistance; Engineering; Epithelial Cells; Fibrous capsule of kidney; Future; Genetic; Goals; Hypoxia Inducible Factor; Hypoxia-Inducible Factor Pathway; Implant; In Vitro; Kidney Transplantation; Malignant Epithelial Cell; Malignant Neoplasms; Mediating; Metastatic Neoplasm to the Kidney; Modeling; Molecular; Molecular Target; Mus; Neoplasm Metastasis; Neoplasms in Vascular Tissue; Pathogenesis; Patients; Pharmacology; Phenotype; Phosphorylation; Pre-Clinical Model; Preclinical Testing; Primary Neoplasm; Production; Prognostic Factor; Radiation therapy; Receptor Protein-Tyrosine Kinases; Renal carcinoma; Resistance; Role; Safety; Signal Pathway; Signal Transduction; Signaling Protein; Site; Specificity; Survival Rate; Testing; Therapeutic Agents; Tumor Angiogenesis; Tumor Burden; Tumor Cell Invasion; Tumor Suppressor Proteins; Tyrosine; Tyrosine Kinase Inhibitor; United States; Up-Regulation; Vascular Endothelial Growth Factors; Work; Xenograft procedure; cancer therapy; clinical candidate; clinical development; comparative efficacy; human model; improved; in vivo; inhibitor/antagonist; mouse model; neoplastic cell; new therapeutic target; novel; novel strategies; novel therapeutics; preclinical study; prevent; public health relevance; receptor; response; small molecule; targeted agent; therapeutic target; therapy development; therapy resistant; tumor; tumor growth; tumor initiation; tumor progression

 DESCRIPTION (provided by applicant): Clear cell renal cell carcinomas (ccRCC), the most common kidney cancers, are highly vascularized tumors that initially respond to antiangiogenic therapies. However, in the majority of patients treated with these agents, the tumor becomes resistant and progresses. Thus, therapies that inhibit additional molecular targets are needed to improve the overall survival rate of patients with metastatic ccRCC patients. We recently discovered that the receptor tyrosine kinase, AXL, is in part regulated by the von Hippel Lindau (VHL) tumor suppressor in ccRCC cell lines. Most importantly, AXL expression in ccRCC patients correlates with the lethal phenotype, strongly indicating an important role for AXL in the pathogenesis of ccRCC. In addition, AXL is an upstream regulator of both SRC and cMET signaling which are independent prognostic factors for poor survival in ccRCC patients. Genetic and pharmacologic inhibition of AXL signaling is sufficient to inhibit ccRCC tumor invasion and metastasis. While these findings establish an important biologic role for AXL in renal metastasis, there is a significant deficit of therapeutic agents that specifically target AXL signaling in the clinic. For this purpose, we produced an ultra-high-affinity soluble AXL (sAXL) FC-fusion protein. In our preclinical studies, we demonstrated that sAXL is a potent and selective inhibitor of GAS6 and is safe in mice. Furthermore, sAXL blocked GAS6 mediated signaling and tumor cell invasion and produced antitumor efficacy in multiple tumor models. We hypothesize that sAXL, an anti-metastatic agent, will be effective in treating sunitinib sensitive and resistant ccRCC and work in combination with antiangiogenic agents to enhance antitumor efficacy in ccRCC. The proposed studies will investigate the efficacy, survival benefit, and safety of sAXL alone or in combination with antiangiogenic agents to support its clinical development for the treatment of advanced ccRCC. To achieve this goal, we will determine the efficacy of our sAXL receptor in sunitinib resistant and sensitive preclinical models and patient derived grafts of kidney cancer (Specific Aim 1). We will also elucidate the mechanisms by which sAXL therapy inhibits the invasive phenotype of ccRCC tumor epithelial cells (Specific Aim 2). In addition, our preliminary data indicate that AXL signaling contributes to VEGF production and the angiogenic phenotype in sunitinib resistant cells. Therefore, we will also determine the role of sAXL therapy on ccRCC tumor angiogenesis (Specific Aim 3). Our final aim will test the hypothesis that, in comparison to the broad acting tyrosine kinase inhibitor cabozantinib, the combination of sAXL and axitinib, an approved second line tyrosine kinase inhibitor for advanced ccRCC, will be safer and more effective in blocking AXL activity in advanced ccRCC tumor growth and progression (Specific Aim 4). We believe that our novel strategy, an engineered form of AXL with enhanced GAS6-binding affinity, specificity, and safety represents a new and therapeutically robust clinical candidate for the treatment of advanced ccRCC.

 描述（由申请人提供）：透明细胞肾细胞癌（ccRCC）是最常见的肾癌，是一种高度血管化的肿瘤，最初对抗血管生成疗法有反应，然而，在大多数用这些药物治疗的患者中，肿瘤变得耐药并且变得耐药。因此，需要抑制其他分子靶点的疗法来提高转移性​​ ccRCC 患者的总生存率。我们最近发现受体酪氨酸激酶 AXL 部分受到调节。 ccRCC 细胞系中的 von Hippel Lindau (VHL) 肿瘤抑制因子最重要的是，ccRCC 患者中的 AXL 表达与致死表型相关，表明 AXL 在 此外，AXL 是 SRC 和 cMET 信号传导的上游调节因子，AXL 信号传导的遗传和药理学抑制足以抑制 ccRCC 肿瘤的侵袭和转移。尽管确定了 AXL 在肾转移中的重要生物学作用，但临床上专门针对 AXL 信号转导的治疗药物明显不足，为此，我们生产了超高亲和力的药物。在我们的临床前研究中，我们证明 sAXL 是一种有效的选择性 GAS6 抑制剂，并且在小鼠中是安全的。此外，sAXL 还能阻断 GAS6 介导的信号传导和肿瘤细胞侵袭，并在多种疾病中产生抗肿瘤功效。我们追求抗转移剂 sAXL 将有效治疗舒尼替尼敏感和耐药的 ccRCC 和 与抗血管生成药物联合使用，以增强 ccRCC 的抗肿瘤功效。拟议的研究将调查 sAXL 单独使用或与抗血管生成药物联合使用的疗效、生存获益和安全性，以支持其治疗晚期 ccRCC 的临床开发。为了实现这一目标，我们将确定 sAXL 受体在舒尼替尼耐药和敏感的临床前模型以及肾癌患者来源的移植物中的功效（具体目标 1）。 sAXL 疗法抑制 ccRCC 肿瘤上皮细胞侵袭表型的机制（具体目标 2）。此外，我们的初步数据表明，AXL 信号传导有助于舒尼替尼耐药细胞中的 VEGF 产生和血管生成表型。 sAXL 疗法对 ccRCC 肿瘤血管生成的作用（具体目标 3）与广泛作用相比，我们的最终目标将检验这一假设。酪氨酸激酶抑制剂卡博替尼 (cabozantinib) 是 sAXL 和阿西替尼 (axitinib) 的组合，是一种已批准用于治疗晚期 ccRCC 的二线酪氨酸激酶抑制剂，将更安全、更有效地阻断晚期 ccRCC 肿瘤生长和进展中的 AXL 活性（具体目标 4）。新颖的策略，一种具有增强的 GAS6 结合亲和力、特异性和安全性的 AXL 工程形式，代​​表了一种新的、治疗性强的临床候选药物，用于治疗晚期ccRCC。

项目成果

Erythropoiesis, EPO, macrophages, and bone.

• DOI: 10.1016/j.bone.2018.03.014
• 发表时间: 2019-03
• 期刊: Bone
• 影响因子: 4.1
• 作者: Eggold JT;Rankin EB
• 通讯作者: Rankin EB

A New Chromatin-Cytoskeleton Link in Cancer.

• DOI: 10.1158/1541-7786.mcr-16-0250
• 发表时间: 2016-12
• 期刊: Molecular cancer research : MCR
• 作者: Giaccia AJ