Arf6 inhibitors for the treatment of uveal melanoma

Arf6抑制剂用于治疗葡萄膜黑色素瘤

• 批准号: 8901672
• 负责人: ALAN L MUELLER
• 金额: $ 29.87万
• 依托单位: NAVIGEN, INC.
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-10 至 2017-04-09
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8901672
• 关键词: ADP-ribosylation factor 6; Adult; Agar; Anchorage-Independent Growth; Animal Model; Area; Biological Assay; Body part; Cell Culture Techniques; Cell Line; Cell Proliferation; Cells; Clinical Trials; Data; Development; Disease; Disease model; Drug Kinetics; Eye; Future; GNAQ gene; Genetic Transcription; Growth; Human; In Vitro; Inflammation; Intraperitoneal Injections; Liver; MEKs; Malignant Neoplasms; Mediating; Melanoma Cell; Methods; Mitogen-Activated Protein Kinases; Molecular; Monomeric GTP-Binding Proteins; Mus; Mutation; Neoplasm Metastasis; Organ; Pathway interactions; Patients; Pharmaceutical Preparations; Phospholipase C; Play; Positioning Attribute; Primary Neoplasm; Protein Kinase C; Proteins; Role; Signal Pathway; Syndrome; Testing; Therapeutic; Tissues; Toxic effect; Transcription Factor AP-1; Universities; Utah; Uveal Melanoma; WNT5A gene; Work; Xenograft Model; Xenograft procedure; base; beta catenin; cell behavior; drug development; effective therapy; efficacy testing; in vivo; inhibitor/antagonist; interest; knock-down; matrigel; melanocyte; mouse model; neoplastic cell; novel; phase 1 study; phase 2 study; public health relevance; small molecule; success; tumor; tumor growth; tumorigenesis

 DESCRIPTION (provided by applicant): Activating mutations in Gα proteins are the drivers of oncogenesis in numerous cancers. Therefore, identifying drugs that block the signaling pathways controlled by these mutations could have enormous therapeutic consequences. Uveal melanoma is a prototypical Gα-driven cancer in which about 80% of tumors have activating mutations in one of two Gα-encoding genes, GNAQ and GNA11. Although progress has been made in the treatment of primary uveal melanoma tumors, metastasis occurs in approximately 50% of patients and once the tumor has spread to other tissues and organs, usually the liver, no current treatments are effective and the disease is invariably fatal. Therefore, finding a treatment that reduces metastasis or can reduce tumor establishment or growth of metastatic uveal melanomas is of utmost importance, especially if the treatment also has therapeutic potential for several other cancers. Activating mutations in GNAQ and GNA11 control at least two major signaling pathways that are important for melanocyte transformation and uveal melanoma growth. These signaling pathways activate mitogen- activated protein kinase/extracellular signal-regulated kinases (MAPK/ERK) and YAP to control AP1- and YAP- TEAD-mediated transcription that leads to transformation and tumor growth. We and our collaborators at the University of Utah have identified the small GTPase ADP-ribosylation factor 6 (ARF6) as a primary immediate effector of constitutively activated GNAQ. Knocking down ARF6 expression or inhibiting its activation with the small molecule compound SecinH3 has the same effect as knocking down constitutively activated GNAQ. We have demonstrated that ARF6 knockdown inhibits the establishment and growth of tumors in an orthotopic xenograft mouse model of uveal melanoma and have preliminary data suggesting that small molecule inhibition of ARF6 likewise reduces tumor formation and growth. These results suggest that ARF6 inhibition may be an effective method for treating both primary and metastatic uveal melanoma. In this Phase I study, we will test our hypothesis by pursuing two aims. In Aim 1, we will determine whether novel ARF6 inhibitors can inhibit proliferation, anchorage-independent colony growth, and invasion of uveal melanoma cells. In Aim 2, we will test the efficacy of our inhibitors in our orthotopic xenograft model of human uveal melanoma. As noted above, Gα proteins play important roles in many cancers. Therefore, results from this Phase I study may have much broader implications for the treatment of multiple cancers. Success will place us in an ideal position to proceed to a Phase II study in which we will continue to examine the efficacy of these compounds in other animal models of uveal melanoma to show general applicability, while also performing pharmacokinetic and detailed toxicity studies. These Phase II studies will be necessary to obtain IND approval and allow for future clinical trials.

 描述（由申请人提供）：Gα 蛋白的激活突变是多种癌症发生的驱动因素。因此，识别阻断这些突变控制的信号通路的药物可能会产生巨大的治疗效果。葡萄膜黑色素瘤是一种典型的 Gα 驱动的癌症，其中约 80% 的肿瘤在两个 Gα 编码基因 GNAQ 和 GNA11 之一中存在激活突变。尽管原发性葡萄膜黑色素瘤的治疗已取得进展，但约 50% 的患者会发生转移，一旦肿瘤扩散到其他组织和器官（通常是肝脏），目前的治疗方法均无效，这种疾病总是致命的。因此，找到一种减少转移或减少肿瘤形成或转移性葡萄膜黑色素瘤生长的治疗方法至关重要，特别是如果该治疗方法还具有治疗其他几种癌症的潜力。 GNAQ 和 GNA11 的激活突变控制至少两条对黑色素细胞转化和葡萄膜黑色素瘤生长很重要的信号传导途径。这些信号通路激活丝裂原激活蛋白激酶/细胞外信号调节激酶 (MAPK/ERK) 和 YAP，以控制 AP1 和 YAP-TEAD 介导的转录，从而导致转化和肿瘤生长。我们和犹他大学的合作者已经确定小 GTP 酶 ADP-核糖基化因子 6 (ARF6) 是组成型激活的 GNAQ 的主要直接效应子。用小分子化合物SecinH3敲低ARF6表达或抑制其激活与敲低组成型激活的GNAQ具有相同的效果。我们已经证明，ARF6 敲低可抑制葡萄膜黑色素瘤原位异种移植小鼠模型中肿瘤的形成和生长，并且初步数据表明 ARF6 的小分子抑制同样会减少肿瘤的形成和生长。这些结果表明ARF6抑制可能是治疗原发性和转移性葡萄膜黑色素瘤的有效方法。 在本第一阶段研究中，我们将通过追求两个目标来检验我们的假设。在目标 1 中，我们将确定新型 ARF6 抑制剂是否可以抑制葡萄膜黑色素瘤细胞的增殖、不依赖贴壁的集落生长和侵袭。在目标 2 中，我们将测试我们的抑制剂在人类葡萄膜黑色素瘤原位异种移植模型中的功效。 如上所述，Gα 蛋白在许多癌症中发挥重要作用。因此，这项一期研究的结果可能对多种癌症的治疗具有更广泛的影响。成功将使我们处于进行 II 期研究的理想位置，我们将继续检查这些化合物在其他葡萄膜黑色素瘤动物模型中的功效，以显示普遍适用性，同时也进行药代动力学和详细的毒性研究。这些 II 期研究对于获得 IND 批准并允许未来的临床试验是必要的。