Development of GPER Agonists as Therapeuticsfor Cutaneous and Uveal Melanoma

GPER 激动剂作为皮肤和葡萄膜黑色素瘤治疗药物的开发

• 批准号: 10602468
• 负责人: TINA GARYANTES
• 金额: $ 200万
• 依托单位: LINNAEUS THERAPEUTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-03-16 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10602468
• 关键词: Advanced Malignant Neoplasm; Agonist; Amendment; Award; Biological Availability; Biopsy; Blocking Antibodies; Businesses; Cancer Center; Canis familiaris; Capital Financing; Clinical; Code; Collaborations; Cutaneous; Cutaneous Melanoma; DNA sequencing; Development; Dose; Enrollment; Estrogens; Evaluable Disease; Formalin; Formulation; Future; GPER gene; Germ-Line Mutation; Goals; Human; Immunohistochemistry; Immunologic Memory; Immunotherapy; Investigational New Drug Application; Lesion; Malignant Neoplasms; Medical; Metastatic Melanoma; Minority; Mus; Oral; Oral Administration; Orphan; Pathway interactions; Patients; Pennsylvania; Pharmaceutical Preparations; Pharmacodynamics; Phase; Phase I Clinical Trials; Polymers; Process; Prognostic Marker; Prolactin; Proto-Oncogene Proteins c-myc; Rattus; Receptor Activation; Recommendation; Refractory; Refrigeration; Resolution; Safety; Signal Transduction; Site; Small Business Innovation Research Grant; Stable Disease; Surface; Tablets; Technology Transfer; Temperature; Testing; Therapeutic; United States; Universities; Uveal Melanoma; Variant; Water; Work; anti-PD-1; antitumor effect; biomarker identification; biomarker panel; biomarker validation; c-myc Genes; cancer type; chemical stability; chemotherapy; clinical efficacy; clinical trial protocol; cohort; combinatorial; commercialization; design; efficacy evaluation; enantiomer; immune-related adverse events; improved; improved outcome; innovation; melanoma; melting; mouse model; neoplastic cell; new therapeutic target; novel; novel therapeutics; patient subsets; pembrolizumab; pharmacologic; phase 1 study; pre-clinical; predictive marker; programmed cell death ligand 1; receptor; receptor expression; response; side effect; small molecule; soft tissue; standard of care; tablet formulation; targeted treatment

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.

项目概要： 尽管免疫和靶向治疗的最新进展极大地改善了结果， 对于许多晚期癌症患者，只有少数患者获得了持久的反应， 并且治疗经常受到严重副作用的限制。迫切需要确定新的 治疗靶点和选择性地与它们结合的有效药理学试剂。口头 可交付的，耐受性良好的，易于合成的小分子癌症治疗剂， 与现有标准护理药物的组合是特别期望的。我们和其他人最近的工作 许多癌症类型被非经典的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）。林奈使用了 第一阶段和第二阶段小企业技术转让（STTR）和小企业创新 研究（SBIR）奖（R41/R44 CA 228695），沿着风险资本资金，以推进GPER 一种名为LNS 8801的激动剂用于人体试验。临床前工作已经确定，（1）LNS 8801具有强效的 在广泛的恶性肿瘤中具有抗肿瘤作用，并且这种活性取决于GPER LNS 8801在肿瘤细胞中的表达;（2）LNS 8801与靶向治疗具有有益的组合效应， （3）LNS 8801在大鼠和狗中具有大的安全窗口。 Linnaeus还开发了LNS 8801的口服生物可利用和可制造的制剂。在一起， 这项工作使我们能够获得研究性新药申请的批准， FDA在抗PD 1难治性黑色素瘤中的跟踪认定; 葡萄膜黑色素瘤;启动多中心I期临床试验（NCT 04130516）并完成剂量递增 在美国的7个癌症中心;并正式与默克公司合作， 派姆单抗迄今为止，28例可评估的难治性晚期癌症患者， 接受LNS 8801单独或与pembrolizumab联合治疗，已被证明是安全和良好的。 在所有剂量水平下均耐受。我们已经观察到LNS 8801处理后c-Myc蛋白的消耗， 验证作用机制。LNS 8801已在几例患者中证明了临床获益， 特别是在皮肤和葡萄膜黑素瘤中。本IIB期提案的目的是进一步 评估皮肤和葡萄膜黑色素瘤的这些初始临床疗效信号，验证预测性和 预后生物标志物，并开发优化的药物产品。实现这些目标将导致 确定在未来关键研究中最有可能从LNS 8801中获益的定义患者亚组 注册试验。