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

 描述(申请人提供)：肾透明细胞癌(CcRCC)，最常见的肾癌，是高度血管化的肿瘤，最初对抗血管生成治疗有反应。然而，在大多数接受这些药物治疗的患者中，肿瘤变得耐药并进展。因此，需要抑制额外分子靶点的治疗来提高转移性肾细胞癌患者的总体存活率。我们最近发现，受体酪氨酸激酶Ax1在一定程度上受ccRCC细胞系中的von Hippel Lindau(VHL)肿瘤抑制因子的调控。最重要的是，Axl在ccRCC患者中的表达与致死性表型相关，强烈表明Axl在CcRCC中的重要作用。 慢性肾细胞癌的发病机制。此外，Ax1是SRC和cMET信号的上游调节因子，而SRC和cMET信号是ccRCC患者生存不良的独立预后因素。AXL信号的遗传和药物抑制足以抑制CcRCC肿瘤的侵袭和转移。虽然这些发现确立了Axl在肾转移中的重要生物学作用，但在临床上还缺乏专门针对Axl信号转导的治疗药物。为此，我们制备了一种超高亲和力的可溶性Axl(Saxl)Fc融合蛋白。在我们的临床前研究中，我们证明了Saxl是一种有效的和选择性的Gas6抑制剂，在小鼠身上是安全的。此外，Saxl还阻断了Gas6介导的信号转导和肿瘤细胞的侵袭，并在多种肿瘤模型中产生了抗肿瘤作用。我们推测，Saxl是一种抗转移药物，将有效地治疗对舒尼替尼敏感和耐药的ccRCC和 与抗血管生成药物联合使用，以提高ccRCC的抗肿瘤疗效。建议的研究将调查Saxl单独或与抗血管生成药物联合应用的有效性、生存效益和安全性，以支持其治疗晚期肾细胞癌的临床开发。为了实现这一目标，我们将确定我们的Saxl受体在对舒尼替尼耐药和敏感的肾癌临床前模型和患者来源的移植物中的有效性(特定目标1)。我们还将阐明Saxl治疗抑制ccRCC肿瘤上皮细胞侵袭性表型的机制(特定目标2)。此外，我们的初步数据表明，Axl信号转导有助于血管内皮生长因子的产生和舒尼替尼耐药细胞的血管生成表型。因此，我们还将确定Saxl治疗对ccRCC肿瘤血管生成的作用(特定目标3)。我们的最终目标将检验这样一个假设，即与广泛作用的酪氨酸激酶抑制剂Cabozantinib相比，Saxl和Axitinib(一种已批准的治疗晚期ccRCC的二线酪氨酸激酶抑制剂)的组合在阻止晚期cRCC肿瘤生长和进展方面将更安全和更有效(特定目标4)。我们相信，我们的新策略，一种工程化形式的Axl，具有增强的Gas6结合亲和力、特异性和安全性，代表了一种治疗晚期肾细胞癌的新的、强大的临床候选方案。

 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.