Novel targeted therapy for treating Ovarian Cancer

项目概要： 卵巢癌（OCa）是美国所有妇科癌症中最致命的。OCa患者最初 对标准的手术和细胞毒性治疗组合有反应;然而，近90%的患者会复发 并且不可避免地会患上耐化疗的疾病。OCa干细胞与肿瘤复发有关 启动和治疗抗性。缺乏促进肿瘤细胞凋亡和消除肿瘤细胞凋亡的靶向治疗。 OCa中的癌症干细胞是一个关键的屏障。学术-工业伙伴关系（AIP）的目标 基金申请的目的是开发一种新的治疗OCa的靶向疗法。通过这项AIP赠款，我们将建立 位于圣安东尼奥的得克萨斯大学卫生部和埃弗拉公司之间的合作框架，一个San 安东尼奥为基础的生物技术，创造一种新的靶向治疗OCa。关于Evestra Inc.的专业知识， 开发新的小分子抑制剂，破坏蛋白质-蛋白质相互作用，我们已经合理地设计了 并合成了一流的白血病抑制因子受体（LIFR）抑制剂EC 359。我们的初步 研究表明，EC 359具有高效降低OCa细胞生长、促进细胞凋亡、减少 干细胞、致敏治疗抗性OCa细胞，并具有体内活性和有利的PK参数。的 本AIP提案的目的是使用GLP方案合成EC 359（克），建立其机制， 识别生物标志物，使用PDX模型进行疗效研究，并进行脱靶筛选研究， 向FDA提交研究性新药（IND）申请。我们的首要假设是 LIFR信号传导在OCa进展中起关键作用，并且用小分子干扰LIF/LIFR信号传导。 抑制剂EC 359将通过促进OCa细胞的凋亡、减少干细胞性和 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， 药物开发协同专业知识，GMP设施的可用性，OCa生物学经验，临床前 模型和地理位置接近。在Aim 1中，我们将通过确定最大值来评估EC 359的可译性。 耐受剂量、毒性、生物分布、使用异种移植物和PDX模型的体内功效，并测试 EC 359与标准化疗的组合。在目标2中，我们将定义EC 359机制， 使用无偏倚的基因组和蛋白质组学方法建立EC 359活性的分子相关性， EC 359降低干性的作用和机制，并确定EC 359在重编程中的作用 在同基因和人源化小鼠模型中的抗OCa免疫，包括巨噬细胞。在目标3中，我们 使用多克规模合成EC 359，进行代谢物研究，进行心血管安全筛选， 并建立配方和化学生产控制。本AIP提案中提出的研究将 建立一种新的靶向治疗方法，消除局部肿瘤生长，减少复发，并提高 OCa患者的生存率。EC 359可用作单一疗法，或用于组合疗法，或用作治疗剂。 维持治疗，从而创造了一个新的范式，新的靶向治疗OCa的治疗。

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.