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

 描述（由申请方提供）：透明细胞肾细胞癌（ccRCC）是最常见的肾癌，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，需要抑制另外的分子靶标的疗法来改善具有转移性ccRCC患者的患者的总体存活率。我们最近发现受体酪氨酸激酶AXL在ccRCC细胞系中部分受von Hippel Lindau（VHL）肿瘤抑制因子调节。最重要的是，ccRCC患者中的AXL表达与致死性表型相关，强烈表明AXL在肾细胞癌中的重要作用。 ccRCC的发病机制。此外，AXL是SRC和cMET信号传导的上游调节剂，这是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学抑制足以抑制ccRCC肿瘤侵袭和转移。虽然这些发现确立了AXL在肾转移中的重要生物学作用，但在临床中特异性靶向AXL信号传导的治疗剂存在显著缺陷。为此，我们产生了超高亲和力可溶性AXL（sAXL）FC融合蛋白。在我们的临床前研究中，我们证明了sAXL是GAS 6的有效和选择性抑制剂，并且在小鼠中是安全的。此外，sAXL阻断GAS6介导的信号传导和肿瘤细胞侵袭，并在多种肿瘤模型中产生抗肿瘤功效。我们假设sAXL，一种抗转移剂，将有效治疗舒尼替尼敏感和耐药的ccRCC， 与抗血管生成剂联合使用以增强ccRCC中的抗肿瘤功效。拟议的研究将研究sAXL单独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，我们将确定我们的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）。我们还将阐明sAXL疗法抑制ccRCC肿瘤上皮细胞的侵袭性表型的机制（特异性目的2）。此外，我们的初步数据表明，AXL信号有助于VEGF的生产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（具体目标3）。我们的最终目的将检验以下假设：与广泛作用的酪氨酸激酶抑制剂卡博替尼相比，sAXL和阿西替尼（一种批准用于晚期ccRCC的二线酪氨酸激酶抑制剂）的组合在阻断晚期ccRCC肿瘤生长和进展中的AXL活性方面将更安全且更有效（具体目的4）。我们相信，我们的新策略，具有增强的GAS6结合亲和力、特异性和安全性的AXL的工程形式，代表了治疗晚期ccRCC的新的和治疗上稳健的临床候选物。

 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.