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

描述（由申请人提供）：眼黑色素瘤是最常见的原发性眼癌。虽然眼睛中的原发性肿瘤可以得到控制，但频繁的癌症扩散到肝脏会导致显著的死亡率。目前还没有有效的治疗方法， 肝脏中的眼部黑素瘤。在疾病的早期/转移前阶段，缺氧诱导眼部肿瘤中趋化因子/生长因子受体的局灶性表达，使得单个黑素瘤细胞响应于其各自的旁分泌配体、基质衍生因子（SDF）和肝细胞生长因子（HGF）在肝脏中产生的活化。在外渗进入循环后，这些细胞回到肝脏，在那里它们最初形成微转移灶，发展为休眠的无血管集落。在疾病晚期，血管生成转换导致形成大的肝巨转移，这导致患者死亡。我们已经发现并表征了新型小分子芳基磺酰胺（ASA）的抗肿瘤特性，并获得了令人兴奋的初步数据，表明我们的先导分子KCN 1可以有效地降低原发性肿瘤的生长，以及我们开发的原位小鼠模型中葡萄膜黑色素瘤肝转移的建立和进展。我们假设KCN 1改变了由CXCR 4/SDF和cMet/HGF介导的促肿瘤发生信号传导，启动转移，阻断了参与肝脏早期进展的STAT 3信号传导和导致大转移的VEGF促血管生成信号传导，因为缺氧诱导因子（HIF）可以调节这些过程，KCN 1阻断HIF转录。我们的目标是确定KCN 1在疾病进展的不同阶段的抗肿瘤作用的机制。我们将确定KCN 1是否抑制i）原发性葡萄膜黑色素瘤细胞外渗和存活进入循环，以及它们归巢到肝脏（目标1），ii）肝脏中微转移灶向无血管性黑色素瘤细胞集落的进展（目标2），以及iii）通过阻断微转移酶诱导的血管生成，抑制肝脏中无血管性黑色素瘤微转移集落向大转移的进展（目标3）。我们的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细胞表面受体激活，STAT 3磷酸化和VEGF介导的肿瘤血管生成。这项工作很重要，因为它将更好地定义葡萄膜黑色素瘤转移的机制，确定治疗靶点，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药物。

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.