Mechanisms of Action for KCN1 in the Control of Uveal Melanoma Metastasis

描述(申请人提供)：眼部黑色素瘤是最常见的原发眼癌。虽然眼部的原发肿瘤可以控制，但频繁的癌症扩散到肝脏会导致相当大的死亡率。目前还没有有效的治疗转移癌的方法。 肝脏的眼部黑色素瘤。在疾病的早期/转移前阶段，低氧诱导眼肿瘤中趋化因子/生长因子受体的局部表达，使单个黑色素瘤细胞对其各自的旁分泌配体、肝脏产生的基质衍生因子(SDF)和肝细胞生长因子(HGF)的激活做出反应。在渗入循环后，这些细胞回到肝脏，在那里它们最初形成微转移灶，然后发展成休眠的无血管集落。在疾病的晚期，血管生成开关导致大的肝脏大转移的形成，从而导致患者死亡。我们已经发现并表征了新型小分子芳基磺胺类化合物(AsAs)的抗肿瘤特性，并获得了令人振奋的初步数据，表明我们的先导分子KCN1可以有效地抑制原发肿瘤的生长，并在我们建立的小鼠原位葡萄膜黑色素瘤模型中抑制葡萄膜黑色素瘤肝转移的建立和进展。我们假设KCN1改变了由CXCR4/SDF和cMET/HGF介导的促肿瘤信号，启动了转移，阻断了参与肝脏早期进展的STAT3信号和导致宏观转移的VEGF促血管生成信号，因为缺氧诱导因子(HIF)可以调节这些过程，KCN1阻止HIF转录。我们建议的目标是确定KCN1在疾病进展的不同阶段发挥抗肿瘤作用的潜在机制(S)。我们将确定KCN1是否抑制：1)原发葡萄膜黑色素瘤细胞的外渗和存活，以及它们在肝脏的归巢(目标1)，2)肝内微转移灶向无血管黑色素瘤细胞集落的进展(目标2)，以及3)通过阻断微转移诱导的血管生成而使无血管黑色素瘤微转移集落在肝脏向大转移的进展(目标3)。我们的初步发现支持我们的工作假设，因为我们证明KCN1在体内抑制cMET细胞表面受体激活、STAT3磷酸化和血管内皮生长因子介导的肿瘤血管生成。这项工作非常重要，因为它将更好地确定葡萄膜黑色素瘤转移的机制，识别治疗靶点，并帮助我们确定的小分子转化为控制葡萄膜黑色素瘤转移的新型治疗剂。

DESCRIPTION (provided by applicant): Ocular melanoma is the most common primary eye cancer. Although the primary tumor in the eye can be controlled, frequent cancer spread to the liver results in significant mortality. There are currently no effective treatments for metastastic ocular melanoma in the liver. In the early/pre-metastatic stage of the disease, hypoxia induces the focal expression of chemokine/growth factor receptors in the eye tumor, rendering single melanoma cells responsive to activation by their respective paracrine ligands, stromal derived factor (SDF) and hepatocyte growth factor (HGF) produced in the liver. After extravasation into the circulation these cells home to the liver where they initially form micrometastatic foci that progress to dormant avascular colonies. In the late disease stage, an angiogenic switch leads to the formation of large hepatic macrometastases, which cause patient demise. We have discovered and characterized the anti-tumor properties of novel small molecule arylsulfonamides (ASAs), and obtained exciting preliminary data demonstrating that KCN1, our lead molecule, can potently decrease primary tumor growth, and the establishment and progression of hepatic metastases of uveal melanoma in an orthotopic mouse model we developed. We hypothesize that KCN1 alters the pro-tumorigenic signaling mediated by CXCR4/SDF and cMet/HGF that initiates metastasis, blocks STAT3 signaling involved in early progression in the liver and VEGF pro-angiogenic signaling that leads to macrometastasis, because Hypoxia Inducible Factor (HIF) can regulate these processes and KCN1 blocks HIF transcription. The goal of our proposal is to define the mechanism(s) underlying the anti-tumor effect of KCN1 at the different stages of disease progression. We will determine whether KCN1 inhibits i) the extravasation and survival of primary uveal melanoma cells into the circulation, and their homing to the liver (Aim 1), ii) the progression of micrometastatic foci to avascular melanoma cell colonies in the liver (Aim 2), and iii) the progression of avascular melanoma micrometastatic colonies to macrometastases in the liver by blocking micrometastases-induced angiogenesis (Aim 3). Our preliminary findings support our working hypothesis, as we demonstrate that KCN1 inhibits cMet cell surface receptor activation, STAT3 phosphorylation, and VEGF-mediated tumor angiogenesis in vivo. This work is important as it will better define the mechanisms of uveal melanoma metastases, identify therapeutic targeting points, and help the translation of the small molecules we identified towards becoming novel therapeutic agents for the control of metastasis of uveal melanoma.