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: 8949353
• 负责人: Amato J. Giaccia
• 金额: $ 50.78万
• 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/8949353
• 关键词: Affinity; Angiogenesis Inhibitors; Antibodies; Binding; Biological Markers; Blood Vessels; Cancer Etiology; Cell Line; Cells; Cessation of life; Chimeric Proteins; Clear Cell; Clinic; Clinical; Combined Modality Therapy; Data; Development; Disease; Disease Resistance; Engineering; Epithelial Cells; Fibrous capsule of kidney; Figs - dietary; Future; Genetic; Goals; Human; Hypoxia Inducible Factor; Hypoxia-Inducible Factor Pathway; Implant; In Vitro; Malignant Epithelial Cell; Malignant Neoplasms; Mediating; Metastatic Neoplasm to the Kidney; Modeling; Molecular; Molecular Target; Mus; Neoplasm Metastasis; Pathogenesis; Patients; Phenotype; Phosphorylation; Pre-Clinical Model; Preclinical Testing; Primary Neoplasm; Production; Prognostic Factor; Radiation therapy; Receptor Protein-Tyrosine Kinases; Renal Cell Carcinoma; 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; comparative efficacy; improved; in vivo; inhibitor/antagonist; mouse model; neoplastic cell; new therapeutic target; novel; novel strategies; 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.