Novel targeted therapy for treating Ovarian Cancer

项目总结： 卵巢癌(OCA)是美国所有妇科癌症中最致命的。最初患有OCA的患者 对手术和细胞毒治疗的标准组合有反应；然而，近90%的人会复发 不可避免地会死于耐化疗的疾病。OCA干细胞与肿瘤复发有关 启动和治疗抵抗。缺乏促进肿瘤细胞凋亡和消除肿瘤细胞的靶向治疗 亚奥理事会中的癌症干细胞代表着一个关键的障碍。这一学术-产业合作伙伴关系(AIP)的目标 GRANT的申请是为治疗OCA开发一种新的靶向治疗方法。通过这笔AIP赠款，我们将建立 德克萨斯大学圣安东尼奥分校和圣安东尼奥Evestra Inc.之间的合作框架 基于安东尼奥的生物技术公司为治疗OCA创造了一种新的靶向疗法。凭借Evestra Inc.的S在 开发破坏蛋白质相互作用的新型小分子抑制剂，我们进行了合理的设计 并合成了一种一流的白血病抑制因子受体(LIFR)抑制剂EC359。我们的预赛 研究表明，EC359具有高效抑制OCA细胞生长、促进细胞凋亡、减少 干细胞，敏化治疗耐药的OCA细胞，并具有体内活性和有利的PK参数。这个 该AIP方案的目的是利用GLP协议合成EC359，建立其作用机制， 识别生物标记物，使用PDX模型进行疗效研究，并进行非靶点筛选研究 需要向FDA提交研究新药(IND)申请。我们最重要的假设是 LIFR信号在OCA的进展中起关键作用，并通过小分子干扰LIF/LIFR信号 抑制剂EC359将通过促进OCA细胞凋亡，减少干性，并具有治疗作用 通过改变肿瘤微环境促进抗肿瘤免疫。我们的AIP团队是独一无二的 药物开发方面的协同专业知识，GMP设施的可用性，OCA生物学的经验，临床前 模特和地理上的接近。在Aim1中，我们将通过确定最大值来评估EC359的可译性 异种移植和PDX模型的耐受量、毒性、生物分布、体内疗效，并测试 EC359联合标准护理化疗。在目标2中，我们将定义EC359机制， 使用无偏见的基因组和蛋白质组方法建立EC359活性的分子关联，定义 EC359减少茎的作用和机制及决定EC359在重编程中的作用 抗OCA免疫，包括巨噬细胞，在同基因和人源化小鼠模型中。在《目标3》中，我们将 使用多克标尺合成EC359，进行代谢物研究，进行心血管安全筛查， 并建立配方和化学制造控制。这项AIP提案中提议的研究将 建立一种新的靶向治疗方法，消除局部肿瘤生长，减少复发，并增强 OCA患者的生存情况。EC359可作为单一疗法、联合疗法或作为一种 维持疗法，从而为OCA的治疗创造了一种新的靶向治疗新范式。

PROJECT SUMMARY: Ovarian cancer (OCa) is the deadliest of all gynecologic cancers in the United States. Patients with OCa initially respond to standard combinations of surgical and cytotoxic therapy; however, nearly 90% will develop recurrence and inevitably succumb to chemotherapy-resistant disease. OCa stem cells are implicated in the tumor re- initiation and therapy resistance. Lack of targeted therapies that promote apoptosis of tumor cells and eliminate cancer stem cells in OCa represents a critical barrier. The goal of this Academic-Industry Partnership (AIP) grant application is to develop a novel targeted therapy for treating OCa. Through this AIP grant, we will establish a collaborative framework between the University of Texas Health at San Antonio and Evestra Inc., a San Antonio based biotech to create a novel targeted therapy for treating OCa. With Evestra Inc.'s expertise in developing novel small molecule inhibitors that disrupt protein-protein interactions, we have rationally designed and synthesized a first-in-class leukemia inhibitory factor receptor (LIFR) inhibitor, EC359. Our preliminary studies have shown that EC359 reduces the growth of OCa cells with high potency, promote apoptosis, reduce stemness, sensitize therapy resistant OCa cells and has in vivo activity with favorable PK parameters. The objective of this AIP proposal is to synthesize EC359 in grams using GLP protocol, establish its mechanisms, identify biomarkers, conduct efficacy studies using PDX models, and perform off target screening studies that are needed to file the Investigational New Drug (IND) Application to FDA. Our overarching hypothesis is that LIFR signaling plays a critical role in OCa progression, and disruption of LIF/LIFR signaling with small molecule inhibitor EC359 will have a therapeutic effect by promoting apoptosis of OCa cells, reducing stemness, and promoting anti-tumor immunity by altering the tumor microenvironment. Our AIP team is unique due to synergistic expertise in drug development, availability of GMP facility, experience with OCa biology, preclinical models and geographic proximity. In Aim1, we will evaluate translatability of EC359 by determining maximum tolerated dose, toxicity, biodistribution, in vivo efficacy using xenografts and PDX models and test the utility of EC359 in combination with standard of care chemotherapy. In Aim 2, we will define EC359 mechanisms, establish molecular correlates of EC359 activity using unbiased genomic and proteomic approaches, define the role and mechanism by which EC359 reduces stemness and determine the role of EC359 in reprogramming the anti-OCa immunity, including macrophages, in syngeneic and humanized mouse models. In Aim 3, we will synthesize EC359 using multi-gram scale, conduct metabolite studies, perform cardiovascular safety screens, and establish formulation and chemistry manufacturing controls. The studies proposed in this AIP proposal will establish a novel targeted therapy that will eliminate local tumor growth, reduce recurrence, and enhance the survival of OCa patients. EC359 could be utilized as a monotherapy, or in combination therapy or as a maintenance therapy, thus creating a new paradigm of novel targeted therapy for the treatment of OCa.