Development of new therapeutic approaches for endometrial cancer

子宫内膜癌新治疗方法的开发

• 批准号: 10688243
• 负责人: SURYAVATHI VISWANADHAPALLI
• 金额: $ 34.75万
• 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: 2022-08-22 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10688243
• 关键词: Affinity; Age Years; Anabolism; Apoptosis; Autocrine Communication; CRISPR/Cas technology; Cancer Etiology; Cancer Patient; Cell model; Cessation of life; Chemicals; Chemoresistance; Chemotherapy and/or radiation; Clear Cell; Clustered Regularly Interspaced Short Palindromic Repeats; Combined Modality Therapy; Complement; Complex; Data Set; Databases; Development; Endometrial Carcinoma; Estrogens; FRAP1 gene; Family; Fertility; Gene Expression Profiling; Genomic approach; Growth; Gynecologic; In Vitro; Incidence; Interleukin-6; LIF gene; Leptin; MAP Kinase Gene; Malignant Neoplasms; Metastatic Neoplasm to Lymph Nodes; Obesity; Obesity Epidemic; Operative Surgical Procedures; Organoids; Pathogenesis; Patients; Pelvic lymph node group; Postoperative Period; Production; Prognosis; Progression-Free Survivals; Proto-Oncogene Proteins c-akt; Radiation therapy; Receptor Signaling; Recurrence; Recurrent Malignant Neoplasm; Recurrent disease; Risk Factors; Role; SDZ RAD; STAT3 gene; Serous; Signal Pathway; Signal Transduction; Testing; The Cancer Genome Atlas; Therapeutic; Uterine Corpus Carcinosarcoma; Woman; Xenograft Model; Xenograft procedure; bevacizumab; cancer cell; cancer recurrence; cancer stem cell; cancer survival; cancer therapy; chemotherapy; clinically actionable; clinically significant; cytokine; design; efficacy testing; experience; glycoprotein 130; high risk; hormone therapy; inhibitor; leukemia inhibitory factor receptor; member; mortality; new therapeutic target; novel therapeutic intervention; older women; patient derived xenograft model; pre-clinical; rational design; receptor expression; response; small molecule inhibitor; standard of care; stemness; targeted treatment; therapeutic target; therapy resistant; transcriptome; tumor; tumor growth; tumor progression; tumor xenograft

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.

项目总结 子宫内膜癌(EC)是女性第四大常见癌症。而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级增长。欧共体是 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危险因素。大约80%的EC属于子宫内膜样癌(EEC)。 (I型)，其余20%由浆液性EC(SEC)、透明细胞EC(CEC)、混合性EC和子宫EC组成 癌肉瘤(UCS)(II型)。手术被广泛用于治疗EC；然而，晚期EC患者往往 经历疾病复发。尽管接受了辅助治疗，这些患者复发的风险很高。 癌症和死亡。对开发新的靶向疗法的需求尚未得到满足 现有针对晚期I型(2级、3级)和II型EC的EC指导疗法。全球基因表达 对癌症数据库的分析显示，EC存活率与白血病抑制之间存在负相关 因子(LIF)及其受体LIFR的表达。此外，肥胖状况是导致肥胖的有效诱因 LIF/LIFR信令。综上所述，这些发现有力地表明LIF/LIFR信号在EC中可能是临床上的 可操作的，靶向LIF/LIFR轴的小分子抑制剂可能会阻止EC的进展。我们最近 开发了一种LIFR的小分子抑制剂EC359，初步研究表明EC359降低了LIFR的 EC细胞高效生长，促进细胞凋亡。临床前异种移植研究表明 EC359能有效抑制EC移植瘤生长，阻断肥胖引起的EC进展。 该提案的目标是建立LIF/LIFR信号对EC的贡献的机制 进展，并测试LIFR抑制剂EC359治疗EC的疗效。我们最重要的假设是 LIF/LIFR信号促进EC进展，LIFR抑制剂EC359发挥有效的 靶向治疗以阻止EC进展。在Aim1中，我们将建立LIF/LIFR信令如何 有助于EC进展，使用全球基因组方法确定LIF/LIFR轴的重要性，测试 EC359降低EC细胞干性和化疗耐药性的作用 哪些肥胖促进了EC中的LIF/LIFR信号转导。在AIM2中，我们将使用以下命令测试阻塞LIF/LIFR轴的效用 EC359使用多个原代和已建立的EC模型细胞，并测试EC359对EC进展的作用 作为单一治疗或与化疗联合使用的异种移植，患者来源的植入物(PDE)， 有机物(PDO)和患者来源的异种移植(PDX)模型。我们还将测试EC359在减少 肥胖驱动的EC。这一建议具有临床意义，因为它将建立一种可译性、 一流的LIFR抑制剂EC359，并实现合理的联合治疗设计。LIFR抑制剂 EC359可以作为单一疗法使用，也可以与标准护理相结合，创造新的 使用EC359作为晚期I型(2级、3级)和II型EC的新靶向治疗的范例。

项目成果

Novel LIPA-Targeted Therapy for Treating Ovarian Cancer.

治疗卵巢癌的新型 LIPA 靶向疗法。

• DOI: 10.3390/cancers16030500
• 发表时间: 2024
• 期刊: Cancers
• 影响因子: 5.2
• 作者: Collier,AlexiaB;Viswanadhapalli,Suryavathi;Gopalam,Rahul;Lee,Tae-Kyung;Kassees,Kara;Parra,Karla;Sharma,Gaurav;Reese,TannerC;Liu,Xihui;Yang,Xue;Ebrahimi,Behnam;Pratap,UdayP;Mahajan,Megharani;Arnold,WilliamC;Baker,Adriana;C
• 通讯作者: C

Inhibition of LIFR Blocks Adiposity-Driven Endometrioid Endometrial Cancer Growth.

• DOI: 10.3390/cancers14215400
• 发表时间: 2022-11-02
• 期刊: CANCERS
• 影响因子: 5.2
• 作者: Blankenship, Logan;Pratap, Uday P.;Yang, Xue;Liu, Zexuan;Altwegg, Kristin A.;Santhamma, Bindu;Ramasamy, Kumaraguruparan;Konda, Swapna;Chen, Yidong;Lai, Zhao;Zheng, Siyuan;Sareddy, Gangadhara R.;Valente, Philip T.;Kost, Edward R.;Nair, Hareesh B.;Tekmal, Rajeshwar R.;Vadlamudi, Ratna K.;Viswanadhapalli, Suryavathi
• 通讯作者: Viswanadhapalli, Suryavathi

The LIFR Inhibitor EC359 Effectively Targets Type II Endometrial Cancer by Blocking LIF/LIFR Oncogenic Signaling.

LIFR抑制剂EC359通过阻止LIF/LIFR致癌信号传导有效地靶向II型子宫内膜癌。

• DOI: 10.3390/ijms242417426
• 发表时间: 2023-12-13
• 期刊: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
• 影响因子: 5.6
• 作者: Spencer, Nicole;Rodriguez Sanchez, Alondra Lee;Gopalam, Rahul;Subbarayalu, Panneerdoss;Medina, Daisy M.;Yang, Xue;Ramirez, Paulina;Randolph, Lois;Aller, Emily Jean;Santhamma, Bindu;Rao, Manjeet K.;Tekmal, Rajeshwar Rao;Nair, Hareesh B.;Kost, Edward R.;Vadlamudi, Ratna K.;Viswanadhapalli, Suryavathi
• 通讯作者: Viswanadhapalli, Suryavathi