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.

 描述（由适用提供）：最常见的肾脏癌（CCRCC）透明细胞肾细胞癌（CCRCC）是高度血管化的肿瘤，最初对抗血管生成疗法有反应。但是，在大多数接受这些药物治疗的患者中，肿瘤变得具有抗性并进展。这需要抑制其他分子靶标的疗法以提高转移性​​CCRCC患者患者的总体存活率。我们最近发现，CCRCC细胞系中的Von Hippel Lindau（VHL）肿瘤抑制剂AXL受体酪氨酸激酶AXL部分受到调节。最重要的是，CCRCC患者的AXL表达与致命表型相关，强烈表明AXL在 CCRCC的发病机理。此外，AXL是SRC和CMET信号传导的上游调节剂，它们是CCRCC患者生存不良的独立预后因素。 AXL信号传导的遗传和药理抑制足以抑制CCRCC肿瘤侵袭和转移。尽管这些发现在肾脏转移中为AXL建立了重要的生物学作用，但在诊所中特别靶向AXL信号的治疗剂存在很大的缺陷。为此，我们生产了超高亲密的固体AXL（SAXL）FC融合蛋白。在我们的临床前研究中，我们证明了SAXL是GAS6的潜在和选择性抑制剂，并且在小鼠中是安全的。此外，SAXL阻止了GAS6介导的信号传导和肿瘤细胞侵袭，并在多个肿瘤模型中产生了抗肿瘤有效性。我们假设一种抗转移剂Saxl将有效治疗舒尼替尼敏感和抗性CCRCC，并且 与抗血管生成剂联合起作用，以提高CCRCC的抗肿瘤效率。拟议的研究将研究单独或与抗血管生成剂的效率，生存益处和安全性，以支持其临床发育以治疗晚期CCRCC。为了实现这一目标，我们将确定我们的saxl受体在抗糖尼替尼抗性和敏感的临床前模型中的效率以及肾癌的患者衍生的移植物（特定的目标1）。我们还将阐明SAXL治疗抑制CCRCC肿瘤上皮细胞的侵入性表型的机制（特定的目标2）。此外，我们的初步数据表明AXL信号传导有助于糖抗抗性细胞中的VEGF产生和血管生成表型。因此，我们还将确定SAXL治疗在CCRCC肿瘤血管生成中的作用（特定目标3）。我们的最终目标将检验以下假设：与广泛的作用酪氨酸激酶抑制剂Cabozantinib相比，Saxl和Axitinib（已批准的第二行酪氨酸激酶抑制剂的SAXL和Axitinib的组合将更加安全，在高级CCRCC肿瘤生长和进展方面的AXL活性方面更加有效，并且更有效。我们认为，我们的新型策略是一种具有增强GAS6结合亲和力，特异性和安全性的AXL的工程形式，代​​表了一种新的且治疗良好的临床候选，用于治疗晚期CCRCC。