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.

项目摘要 子宫内膜癌（EC）是女性中第四大常见的癌症。尽管EC最常见于较老的 妇女，40岁以下的妇女的死亡率和发病率正在成倍增加。 EC是 估计每年增加1-2％，而超过一半的EC病例归因于肥胖症，这 被认为是独立的危险因素。大约80％的EC属于子宫内膜类药物EC（EEC） （I型），其余20％的浆液EC（SEC），Clear Cell EC（CEC），混合EC和子宫完成 癌肉瘤（UCS）（II型）。手术被广泛用于治疗EC；但是，患有晚期EC的患者经常 体验疾病缓解。尽管接受了辅助疗法，但这些患者仍处于重复的高风险 癌症和死亡。完成新的靶向疗法有未满足的需求 现有的EC指导疗法用于高级I型（2、3）和II型EC。全球基因表达 对癌症数据库的分析显示，EC生存与白血病之间存在负相关性 因子（LIF）及其受体LIFR表达。此外，肥胖条件是潜在的诱导剂 LIF/LIFR信号。总之，这些发现强烈表明EC中的LIF/LIFR信号可能在临床上是 用较小的分子抑制剂靶向LIF/LIFR轴可能会阻止EC进展。我们最近 开发了LIFR的小分子抑制剂EC359和初步研究表明，EC359降低了 EC细胞具有高效力并促进凋亡的生长。临床前的异种移植研究表明， EC359在减少EC型肿瘤生长并阻止肥胖驱动的EC进展方面高效。 该提案的目的是建立LIF/LIFR信号有助于EC的机制 进展并测试LIFR抑制剂EC359在治疗EC中的效率。我们的总体假设是 该LIF/LIFR信号传导促进EC的进展，而LIFR抑制剂EC359起有效的作用 有针对性的治疗以阻止EC进展。在AIM1中，我们将建立LIF/LIFR信号的机制 有助于EC进展，使用全局基因组方法定义LIF/LIFR轴的重要性，测试 EC359在降低EC细胞的干性和化学耐药性中的效率，研究了通过 肥胖促进EC中的LIF/LIFR信号。在AIM2中，我们将测试使用使用LIF/LIFR轴的实用性 EC359使用多个主要和已建立的EC模型细胞并测试EC359在EC进展中的效用 作为一种单一疗法或与化学疗法的结合，使用Xenographymics，患者衍生的外植体（PDE）， 器官（PDO）和患者衍生的Xenographic（PDX）模型。我们还将测试EC359在还原方面的效用 肥胖驱动的EC。该建议在临床上具有重要意义，因为它将建立可翻译性，机制 一流的LIFR抑制剂EC359，并可以合理地设计组合疗法。 LIFR抑制剂 EC359可以用作单一疗法，也可以与护理标准组合疗法，从而创建一个新的 使用EC359作为晚期I型（2，3）和II型EC的新型靶向疗法的范式。

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

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

• 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

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