Development of new therapeutic approaches for endometrial cancer

项目摘要 子宫内膜癌（EC）是女性第四大常见癌症。虽然EC最常见于老年人， 在妇女中，40岁以下妇女的死亡率和发病率呈指数增长。EC是 估计每年增加1-2%，超过一半的EC病例可归因于肥胖， 被认为是一个独立的风险因素。约80%的EC属于类维生素C EC（EEC） (type其余20%由浆液性EC（SEC）、透明细胞EC（CEC）、混合EC和子宫内膜EC组成。 癌肉瘤（UCS）（II型）。手术广泛用于治疗EC;然而，晚期EC患者通常 经历疾病复发。尽管接受了预防性治疗，这些患者仍有很高的复发风险 癌症和死亡。开发新的靶向疗法的需求尚未得到满足， 针对晚期I型（2、3级）和II型EC的现有EC导向疗法。全球基因表达 对癌症数据库的分析揭示了EC存活率和白血病抑制率之间的负相关性。 LIF及其受体LIFR的表达。此外，肥胖状况作为肥胖的有效诱导物起作用。 LIF/LIFR信号传导。总之，这些发现有力地表明EC中的LIF/LIFR信号传导可能在临床上是重要的。 可作用的，并且用小分子抑制剂靶向LIF/LIFR轴可以阻断EC进展。我们最近 开发了一种LIFR的小分子抑制剂EC 359，初步研究表明EC 359可以降低LIFR的表达。 促进EC细胞高效生长并促进细胞凋亡。临床前异种移植研究表明， EC 359在减少EC异种移植肿瘤生长和阻断由肥胖驱动的EC进展方面非常有效。 本提案的目的是建立LIF/LIFR信号通路促进EC的机制。 进展并测试LIFR抑制剂EC 359在治疗EC中的功效。我们的首要假设是 LIF/LIFR信号传导促进EC进展，并且LIFR抑制剂EC 359作为有效的抑制剂发挥作用。 靶向治疗以阻断EC进展。在Aim 1中，我们将建立LIF/LIFR信号转导的机制， 有助于EC进展，使用全局基因组方法定义LIF/LIFR轴的意义，测试 EC 359在降低EC细胞的干细胞性和化疗耐药性方面的功效， 肥胖促进EC中LIF/LIFR信号传导。在Aim 2中，我们将测试使用以下参数阻塞LIF/LIFR轴的效用： 使用多个原代和建立的EC模型细胞测定EC 359，并测试EC 359对EC进展的效用 作为单一疗法或与使用异种移植物，患者来源的外植体（PDE）， 类器官（PDO）和患者来源的异种移植物（PDX）模型。我们还将测试EC 359在降低 肥胖驱动的EC。这一建议具有临床意义，因为它将建立可翻译性， LIFR抑制剂EC 359是同类产品中的第一种，能够合理设计联合治疗。LIFR抑制剂 EC 359可用作单一疗法，或与标准治疗联合治疗，创造了一种新的治疗方法。 使用EC 359作为晚期I型（2、3级）和II型EC的新型靶向治疗的范例。

PROJECT SUMMARY Endometrial cancer (EC) is the fourth most common cancer in women. While EC occurs most commonly in older women, the mortality rate and incidence is exponentially increasing in women under 40 years of age. EC is estimated to increase by 1–2% yearly and more than half of EC cases are attributable to obesity, which is recognized as an independent risk factor. Approximately 80% of EC belong to the endometrioid EC (EEC) (type I) and the remaining 20% is comprised of serous EC (SEC), clear cell EC (CEC), mixed EC, and uterine carcinosarcoma (UCS) (type II). Surgery is widely used to treat EC; however, patients with advanced EC often experience disease relapse. Despite receiving adjunctive therapy, these patients are at high risk of recurrence of cancer and death. There is an unmet need for the development of new targeted therapies that complement existing EC-directed therapies for advanced type I (grade 2, 3) and type II EC. The global gene expression analysis of the cancer databases revealed a negative correlation between EC survival and Leukemia inhibitory factor (LIF) and its receptor, LIFR expression. Further, obesity conditions function as potent inducers of the LIF/LIFR signaling. Together, these findings strongly suggest that LIF/LIFR signaling in EC may be clinically actionable, and targeting LIF/LIFR axis with a small molecule inhibitor may block EC progression. We recently developed a small molecule inhibitor of LIFR, EC359 and preliminary studies show that EC359 reduces the growth of EC cells with high potency and promotes apoptosis. The preclinical xenograft studies showed that EC359 is highly efficacious in reducing EC xenograft tumor growth and block EC progression driven by obesity. The objective of this proposal is to establish the mechanisms by which LIF/LIFR signaling contributes to EC progression and to test the efficacy of the LIFR inhibitor EC359 in treating EC. Our overarching hypothesis is that LIF/LIFR signaling promotes EC progression, and that the LIFR inhibitor EC359 functions as an effective targeted therapy to block EC progression. In Aim1, we will establish the mechanisms of how LIF/LIFR signaling contributes to EC progression, define the significance of LIF/LIFR axis using global genomic approaches, test the efficacy of EC359 in reducing stemness and chemoresistance of EC cells, investigate the mechanisms by which obesity promote LIF/LIFR signaling in EC. In Aim2, we will test the utility of blocking the LIF/LIFR axis with EC359 using multiple primary and established EC model cells and test the utility of EC359 on EC progression as a monotherapy or combination with chemotherapy using xenografts, patient-derived explants (PDE), organoids (PDO) and patient-derived xenograft (PDX) models. We will also test the utility of EC359 in reducing obesity-driven EC. This proposal is clinically significant because it will establish translatability, mechanisms of a first-in-class LIFR inhibitor, EC359, and enable a rational design of combination therapies. The LIFR inhibitor EC359 can be utilized as a monotherapy, or in combination therapy with the standard-of-care, creating a new paradigm using EC359 as a novel targeted therapy for advanced type I (grade 2, 3) and type II EC.