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

KCN1 控制葡萄膜黑色素瘤转移的作用机制

• 批准号: 9178062
• 负责人: Hans E. Grossniklaus
• 金额: $ 32.37万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-12-15 至 2018-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9178062
• 关键词: Acinus organ component; Address; Affect; Angiogenic Factor; Angiogenic Switch; Animal Model; Blood Circulation; Blood Vessels; CXCR4 gene; Cell Proliferation; Cell Surface Receptors; Cells; Cessation of life; Chemotactic Factors; Data; Development; Disease; Disease Progression; Endothelial Cells; Equilibrium; Event; Extravasation; Eye; Eye Neoplasms; Gelatinase A; Genetic Transcription; Goals; Growth; Growth Factor; Growth Factor Receptors; HGF gene; Health; Hematogenous; Hepatic; Home environment; Homing; Human; Hypoxia; Hypoxia Inducible Factor; In Vitro; Knowledge; Lead; Ligands; Liver; MMP2 gene; Malignant - descriptor; Malignant Neoplasms; Matrix Metalloproteinases; Measures; Mediating; Melanoma Cell; Metastatic Neoplasm to the Liver; Micrometastasis; Molecular; Neoplasm Metastasis; Neoplasms in Vascular Tissue; Ocular Melanoma; Paracrine Communication; Patients; Pharmacological Treatment; Phosphorylation; Physiological; Primary Neoplasm; Process; Production; Property; Receptor Activation; Regulation; STAT3 gene; Signal Transduction; Testing; Therapeutic Agents; Time; Transcriptional Activation; Translations; Tube; Tumor Angiogenesis; Tumorigenicity; Uveal Melanoma; Vascular Endothelial Cell; Vascular Endothelial Growth Factors; Work; angiogenesis; antitumor effect; base; cell motility; chemokine; chemokine receptor; cytokine; effective therapy; expression vector; improved; in vivo; malignant neoplasm of eye; melanocyte; melanoma; metastatic process; migration; mortality; mouse model; neoplastic cell; new therapeutic target; novel; novel therapeutics; paracrine; pigment epithelium-derived factor; prevent; promoter; public health relevance; receptor; research clinical testing; small hairpin RNA; small molecule; therapeutic target; transcription factor; tumor; tumor growth; tumorigenic

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.

描述（由申请人提供）：眼黑色素瘤是最常见的原发性眼癌。尽管眼睛的原发肿瘤可以得到控制，但癌症频繁扩散到肝脏会导致显着的死亡率。目前尚无针对转移性肿瘤的有效治疗方法 肝脏眼部黑色素瘤。在疾病的早期/转移前阶段，缺氧会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、肝脏中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。外渗到循环系统后，这些细胞回到肝脏，在那里它们最初形成微转移灶，并进展为休眠的无血管集落。在疾病晚期，血管生成转换导致大的肝脏巨转移的形成，从而导致患者死亡。我们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，证明我们的先导分子 KCN1 可以在我们开发的原位小鼠模型中有效减少原发性肿瘤生长以及葡萄膜黑色素瘤肝转移的建立和进展。我们假设 KCN1 改变由 CXCR4/SDF 和 cMet/HGF 介导的启动转移的促肿瘤信号传导，阻断参与肝脏早期进展的 STAT3 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，并且 KCN1 阻断 HIF 转录。我们提案的目标是确定 KCN1 在疾病进展的不同阶段抗肿瘤作用的机制。我们将确定 KCN1 是否抑制 i) 原发性葡萄膜黑色素瘤细胞外渗和存活到循环中，以及它们归巢到肝脏（目标 1），ii) 微转移灶向肝脏中无血管黑色素瘤细胞集落的进展（目标 2），以及 iii) 通过阻断无血管黑色素瘤微转移集落向肝脏中大转移的进展 微转移诱导的血管生成（目标 3）。我们的初步研究结果支持了我们的工作假设，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 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剂。