Arf6 inhibitors for the treatment of uveal melanoma

 描述（由申请方提供）：Gα蛋白的激活突变是许多癌症中肿瘤发生的驱动因素。因此，确定阻断由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GNA 11中的一个中具有激活突变。虽然在原发性葡萄膜黑色素瘤的治疗方面已经取得了进展，但转移发生在大约50%的患者中，并且一旦肿瘤扩散到其他组织和器官，通常是肝脏，目前的治疗方法是无效的，并且该疾病总是致命的。因此，找到一种减少转移或可以减少转移性葡萄膜黑色素瘤的肿瘤建立或生长的治疗方法是至关重要的，特别是如果该治疗方法对其他几种癌症也具有治疗潜力。 GNAQ和GNA 11中的激活突变控制至少两个对黑素细胞转化和葡萄膜黑色素瘤生长重要的主要信号通路。这些信号传导途径激活有丝分裂原活化蛋白激酶/细胞外信号调节激酶（MAPK/ERK）和雅普以控制AP 1和雅普-TEAD介导的转录，从而导致转化和肿瘤生长。我们和我们在犹他州大学的合作者已经确定了小GTP酶ADP-核糖基化因子6（ARF 6）作为组成性激活GNAQ的主要直接效应子。用小分子化合物SecinH 3敲低ARF 6表达或抑制其活化与敲低组成型活化的GNAQ具有相同的效果。我们已经证明，在葡萄膜黑色素瘤的原位异种移植小鼠模型中，ARF 6敲低抑制肿瘤的形成和生长，并且初步数据表明，ARF 6的小分子抑制同样减少肿瘤的形成和生长。这些结果表明，抑制ARF 6可能是治疗原发性和转移性葡萄膜黑色素瘤的有效方法。 在第一阶段的研究中，我们将通过追求两个目标来测试我们的假设。在目标1中，我们将确定新的ARF 6抑制剂是否可以抑制葡萄膜黑色素瘤细胞的增殖，锚定非依赖性集落生长和侵袭。在目标2中，我们将测试我们的抑制剂在我们的人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I期研究的结果可能对多种癌症的治疗具有更广泛的意义。成功将使我们处于进行II期研究的理想位置，在该研究中，我们将继续检查这些化合物在葡萄膜黑色素瘤的其他动物模型中的疗效，以显示其普遍适用性，同时还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批准和允许未来的临床试验是必要的。

 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.