Development of GPER Agonists as Therapeuticsfor Cutaneous and Uveal Melanoma

项目总结： 尽管免疫和靶向治疗的最新进展显著改善了结果 对于许多晚期癌症患者来说，只有少数患者取得了持久的反应， 而且治疗经常受到严重副作用的限制。迫切需要找出新的 治疗靶点和选择性地使用它们的有效药理制剂。口服 可交付、耐受性好且易于合成的小分子癌症治疗药物 尤其需要与现有的标准护理药物相结合。我们和其他人最近的工作 证实了许多癌症类型被非经典雌激素信号通过广泛的 表达的表面受体称为G蛋白偶联雌激素受体(GPER)。林奈已经用过 第一阶段和第二阶段小型企业技术转让(STTR)和小型企业创新 研究(SBIR)奖(R41/R44 CA228695)，以及风险资本资金，以推进GPER 激动剂LNS8801进行人体试验。临床前研究表明：(1)LNS8801具有较强的免疫原性 抗肿瘤作用遍及多种恶性肿瘤，这种活性依赖于GPER 在肿瘤细胞中表达；(2)LNS8801与靶向治疗具有有益的联合作用， (3)LNS8801在大鼠和狗身上有很大的安全窗口。 Linneeus还开发了一种口服生物利用度和可制造的LNS8801配方。一起， 这项工作使我们能够获得调查性新药申请的批准以及快速 跟踪FDA对抗PD1难治性黑色素瘤的指定； 葡萄膜黑色素瘤；启动多部位1期临床试验(NCT04130516)和完全剂量递增 在美国的7个癌症中心；并正式确定与默克公司的药物供应合作 培布罗利珠单抗。到目前为止，28名治疗难治性晚期癌症的可评估患者 接受LNS8801单独或与培溴利珠单抗联合使用，已被证明是安全和良好的 在所有剂量水平下都能耐受。我们观察到LNS8801治疗后c-Myc蛋白的耗竭， 验证作用机制。LNS8801已在几名患者中显示出临床益处， 尤其是皮肤和葡萄膜黑色素瘤。这项IIB阶段提案的目的是进一步 评估这些皮肤和葡萄膜黑色素瘤的初步临床疗效信号，验证预测性和 预测预后的生物标志物，并开发优化的药物产品。完成这些目标将导致 确定未来Pivotal中最有可能受益于LNS8801的已定义患者亚组 注册审判。

Project Summary: Although recent advances in immune and targeted therapies have dramatically improved outcomes for many patients with advanced cancer, durable responses are achieved in only a minority of patients, and treatment is frequently limited by significant side effects. There is an urgent need to identify new therapeutic targets and efficacious pharmacologic agents that selectively engage them. Orally deliverable, well-tolerated, and easily synthesized small molecule cancer therapeutics that work in combination with existing standard-of-care drugs are especially desired. Recent work by us and others established that many cancer types are inhibited by nonclassical estrogen signaling through a widely expressed surface receptor called G protein-coupled estrogen receptor (GPER). Linnaeus has used Phase I and Phase II Small Business Technology Transfer (STTR) and Small Business Innovation Research (SBIR) awards (R41/R44 CA228695), along with venture capital funding, to advance a GPER agonist called LNS8801 to human trials. Preclinical work has established that (1) LNS8801 has potent antitumor effects across a wide range of malignancies and that this activity depends on GPER expression in the tumor cells; (2) LNS8801 has beneficial combinatorial effects with targeted therapies, chemotherapies, and immunotherapies; and (3) LNS8801 has a large safety window in rats and dogs. Linnaeus also developed an orally bioavailable and manufacturable formulation of LNS8801. Together, this work enabled us to receive clearance of an Investigational New Drug Application as well as Fast Track designation from the FDA in anti-PD1 refractory melanoma; Orphan Designation from the FDA in uveal melanoma; initiate a multisite phase 1 clinical trial (NCT04130516) and complete dose escalation at 7 cancer centers in the United States; and formalize a drug supply collaboration with Merck for pembrolizumab. To date, 28 evaluable patients with treatment-refractory advanced cancer have received LNS8801 either alone or in combination with pembrolizumab, which has proven safe and well tolerated at all dose levels. We have observed depletion of c-Myc protein after LNS8801 treatment, validating the mechanism of action. LNS8801 has demonstrated clinical benefit in several patients, particularly in cutaneous and uveal melanoma. The purpose of this Phase IIB proposal is to further evaluate these initial clinical efficacy signals in cutaneous and uveal melanoma, validate predictive and prognostic biomarkers, and to develop optimized drug product. Completion of these aims will result in the identification of defined patient subgroups most likely to benefit from LNS8801 in future pivotal registration trials.