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

眼黑色素瘤是最常见的原发性眼癌。虽然原发性肿瘤在 如果眼睛不能得到控制，癌症经常扩散到肝脏，导致死亡率很高。那里 目前还没有有效的治疗肝脏中的恶性眼黑色素瘤的方法。在 在疾病的早期/转移前阶段，缺氧诱导了 眼部肿瘤中的趋化因子/生长因子受体， 对它们各自的旁分泌配体、基质衍生因子（SDF）和 肝细胞生长因子（HGF）是肝脏中产生的。外渗进入循环后 这些细胞回到肝脏，在那里它们最初形成微转移灶， 休眠的无血管菌落在疾病晚期，血管生成开关导致 形成大的肝巨转移，导致患者死亡。我们已经发现 并表征了新型小分子芳基磺酰胺（ASA）的抗肿瘤性质， 并获得了令人兴奋的初步数据，表明我们的先导分子KCN 1可以 有效地减少原发性肿瘤的生长，以及肝细胞癌的建立和发展。 葡萄膜黑色素瘤转移的原位小鼠模型，我们开发。我们假设 KCN 1改变了CXCR 4/SDF和cMet/HGF介导的促肿瘤发生信号， 启动转移，阻断参与肝脏早期进展的STAT 3信号传导， 促血管生成信号，导致大转移，因为缺氧诱导因子 (HIF)可以调节这些过程，KCN 1阻断HIF转录。我们的目标 建议是定义KCN 1在不同水平下的抗肿瘤作用的机制。 疾病进展的阶段。我们将确定KCN 1是否抑制i）外渗 以及原发性葡萄膜黑色素瘤细胞进入循环系统的存活，以及它们归巢到肝脏 (Aim ii）微转移灶向无血管性黑素瘤细胞集落的进展， 肝脏（目标2），和iii）无血管性黑色素瘤微转移集落的进展， 通过阻断微血管酶诱导的血管生成来抑制肝脏中的大转移（Aim 3）。我们 初步研究结果支持我们的工作假设，因为我们证明KCN 1抑制cMet， 细胞表面受体活化、STAT 3磷酸化和VEGF介导的肿瘤 体内血管生成。这项工作很重要，因为它将更好地定义葡萄膜的机制， 黑色素瘤转移，确定治疗靶点，并帮助翻译的小 我们鉴定的分子有望成为控制转移的新型治疗剂， 葡萄膜黑色素瘤

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.