Novel targeted therapy for treating Ovarian Cancer

治疗卵巢癌的新型靶向疗法

• 批准号: 10522920
• 负责人: Hareesh Babu Nair
• 金额: $ 68.9万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10522920
• 关键词: Affinity; Apoptosis; Applications Grants; Biodistribution; Biological; Biological Markers; Biotechnology; Cancer Biology; Cancer Patient; Cardiovascular system; Cell model; Chemicals; Chemistry; Chemoresistance; Clinical Treatment; Clinical Trials; Collaborations; Combined Modality Therapy; Complex; Cytotoxic Chemotherapy; Data; Data Set; Development; Disease Resistance; Dose; Environment; Exhibits; FRAP1 gene; Family; Formulation; Genomics; Geography; Goals; Grant; Growth; Health; IL6ST gene; In Vitro; Industry; Interleukin-6; Investigational Drugs; Investigational New Drug Application; LIF gene; Ligands; MAP Kinase Gene; Maintenance Therapy; Malignant Female Reproductive System Neoplasm; Malignant neoplasm of ovary; Maximum Tolerated Dose; Modeling; Molecular; Neoplasm Metastasis; Operative Surgical Procedures; Patients; Pharmaceutical Preparations; Play; Pre-Clinical Model; Proteomics; Proto-Oncogene Proteins c-akt; Protocols documentation; Receptor Signaling; Recurrence; Research; Resistance; Role; STAT3 gene; Safety; Signal Pathway; Signal Transduction; Testing; Texas; The Cancer Genome Atlas; Therapeutic; Therapeutic Effect; Toxic effect; Translations; Tumor Immunity; United States; Universities; Xenograft Model; Xenograft procedure; base; cancer cell; cancer stem cell; cancer survival; chemotherapy; clinically actionable; clinically significant; drug development; efficacy study; experience; glycoprotein 130; humanized mouse; in vivo; industry partner; inhibitor; leukemia inhibitory factor receptor; macrophage; member; method development; mouse model; neoplastic cell; new therapeutic target; novel; novel therapeutics; oncostatin M; protein protein interaction; rational design; receptor-mediated signaling; screening; small molecule inhibitor; standard of care; stemness; targeted treatment; therapy resistant; tumor; tumor growth; tumor microenvironment; tumor progression

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.

项目概要： 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%会复发 并不可避免地死于化疗耐药性疾病。 OCa 干细胞与肿瘤复发有关 起始和治疗抵抗。缺乏促进肿瘤细胞凋亡和消除肿瘤细胞的靶向治疗 OCa 中的癌症干细胞是一个关键屏障。学术与产业合作伙伴关系 (AIP) 的目标 拨款申请旨在开发一种治疗 OCa 的新型靶向疗法。通过这项 AIP 拨款，我们将建立 德克萨斯大学圣安东尼奥分校健康中心与圣安东尼奥市 Evestra Inc. 之间的合作框架 Antonio 基于生物技术开发了一种治疗 OCa 的新型靶向疗法。凭借 Evestra Inc. 的专业知识 为了开发破坏蛋白质-蛋白质相互作用的新型小分子抑制剂，我们合理地设计了 并合成了首创的白血病抑制因子受体（LIFR）抑制剂EC359。我们的初步 研究表明，EC359 高效能降低 OCa 细胞的生长，促进细胞凋亡，减少 干性，使治疗耐药的 OCa 细胞敏感，并具有良好的 PK 参数的体内活性。这 该 AIP 提案的目标是使用 GLP 协议以克为单位合成 EC359，建立其机制， 识别生物标志物，使用 PDX 模型进行功效研究，并进行脱靶筛选研究 需要向 FDA 提交新药研究 (IND) 申请。我们的总体假设是 LIFR 信号传导在 OCa 进展以及小分子干扰 LIF/LIFR 信号传导中发挥着关键作用 抑制剂EC359将通过促进OCa细胞凋亡、减少干细胞性来发挥治疗作用， 通过改变肿瘤微环境来促进抗肿瘤免疫。我们的 AIP 团队是独一无二的，因为 药物开发方面的协同专业知识、GMP 设施的可用性、OCa 生物学经验、临床前 模型和地理邻近性。在目标 1 中，我们将通过确定最大值来评估 EC359 的可译性 使用异种移植物和 PDX 模型评估耐受剂量、毒性、生物分布、体内功效，并测试其效用 EC359 与标准护理化疗相结合。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 活性的分子相关性，定义 EC359降低干性的作用和机制并确定EC359在重编程中的作用 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，我们将 使用多克规模合成 EC359，进行代谢物研究，进行心血管安全筛查， 并建立配方和化学生产控制。本 AIP 提案中提出的研究将 建立一种新的靶向疗法，消除局部肿瘤生长，减少复发，并增强疗效 OCa 患者的生存率。 EC359 可用作单一疗法、联合疗法或作为 维持治疗，从而开创了OCa治疗的新型靶向治疗的新范例。