Neuroendocrine differentiation post anti-androgenic therapy: Role of Tribbles 2

抗雄激素治疗后的神经内分泌分化：Tribbles 2 的作用

基本信息

批准号：
10659525
负责人：
JAGADANANDA GHOSH
金额：
$ 34.77万
依托单位：
HENRY FORD HEALTH SYSTEM
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-20 至 2028-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10659525
关键词：
Address Adenocarcinoma Age Androgen Antagonists Androgen Receptor Apoptosis Binding Bypass Cancer Cell Growth Castrate sensitive prostate cancer Castration Cell Culture Techniques Cell Line Cells Cessation of life Characteristics Chromogranin A Clinic Clinical Development Distant Metastasis Dose EZH2 gene Environment Epithelium Exons FDA approved Family Gene Chips Gene Expression Gene Expression Profiling Gene Targeting Generations Goals Health Image Immunoprecipitation In Vitro Injections Kidney Knock-out Knockout Mice Knowledge LNCaP Link Liver Luciferases Lung Malignant neoplasm of prostate Mass Spectrum Analysis Measures Medical Metastatic to Modeling Molecular Molecular Target Monitor Movement Mus Neoplasm Metastasis Neuroendocrine Therapy Neuron-Specific Enolase Neurons Neurosecretory Systems Pathologic Patients Phenotype Play Population Prevention Prostate Prostate Neuroendocrine Neoplasm Prostatic Neoplasms Proteins Public Health Regimen Regulation Research Resistance Role SCID Mice Sampling Seminal Synaptophysin TP53 gene Testing Therapeutic Transgenic Mice Transgenic Organisms Up-Regulation Work Xenograft procedure abiraterone androgenic bone cell killing cell type clinically relevant design effective therapy enzalutamide in vivo in vivo Model inhibitor knock-down knockout gene male member molecular marker molecular targeted therapies mouse model multicatalytic endopeptidase complex neuroendocrine differentiation neuroendocrine phenotype new therapeutic target novel overexpression pre-clinical profiles in patients prostate cancer cell prostate cancer cell line prostate cancer model prostate cancer progression receptor function therapy development therapy resistant transcription factor transdifferentiation tumor tumor growth tumor progression

项目摘要

Anti-androgenic therapy is the mainstay for both primary and disseminated forms of prostate cancer. FDA- approved enzalutamide (Xtandi) is at the forefront of anti-androgens with superior patient profile and is the one most prescribed. However, enzalutamide resistant prostate cancer (ERPC) invariably develops, which is incurable and responsible for most of the prostate cancer-related deaths, underscoring that management of ERPC is an unmet and urgent medical need. Development of an effective therapy against ERPC is suffering from lack of proper understanding about critical molecular targets to effectively kill ERPC cells. To identify potential new targets, we developed an ERPC model which mimics the clinical conditions in patients undergoing standard enzalutamide therapy. We treated androgen-sensitive prostate cancer cells with enzalutamide in long- term culture to generate cell lines (LNCaP-ENR, PCa-2B-ENR) which are no longer sensitive to clinically relevant doses of enzalutamide. Comprehensive gene expression analysis revealed that the ERPC cells overexpress Tribbles 2 (Trib2), a member of the tribbles pseudokinase family. Overexpression of Trib2 was also found in PDX and patient prostate tumors after enzalutamide treatment. Forced overexpression Trib2 results in enhanced prostate cancer cell growth and resistance to enzalutamide, apalutamide, darolutamide and abiraterone. Inhibition of Trib2 re-sensitizes resistant cells to enzalutamide and decreases their viability, indicating a possible direct link between Trib2 and development of enzalutamide resistance. Interestingly, Trib2 downregulates Rb1 and p53, while induces the neuronal transcription factors (N-Myc, BRN2) and the neuroendocrine (NE) markers (Chromogranin A, Neuron-specific enolase and Synaptophysin). Inhibition of N-Myc or BRN2 re-sensitizes resistant cells to enzalutamide. These findings suggest that Trib2 drives cellular trans-differentiation from luminal to NE phenotype to pose resistance to anti-androgens. Thus, Trib2 emerges as a novel, promising molecular target for therapy of ERPC-NE. However, the mechanism and role of Trib2 in NE differentiation needs to be determined using appropriate in vitro and in vivo models. Thus, this proposal has been designed which will characterize how Trib2 induces NE differentiation (Aim 1), determine the impact of Trib2 inhibition in enhanced ERPC tumor growth and distant metastasis (Aim 2), and test the impact of Trib2 gene-targeting on prostate tumor progression and NE differentiation using transgenic Trib2 knockout mouse models (Aim 3). Accomplishing these goals will establish Trib2 as a molecular driver for treatment-induced NE differentiation and will help develop a new targeted therapeutic strategy for enzalutamide resistant, NE type, lethal prostate cancer.

抗雄激素治疗是原发性和播散性前列腺癌的主要治疗方法。 FDA- 批准的恩杂鲁胺 (Xtandi) 处于抗雄激素药物的前沿，具有卓越的患者特征，是大多数规定。然而，恩杂鲁胺耐药性前列腺癌 (ERPC) 总是会发展，这是这是无法治愈的，并且是大多数前列腺癌相关死亡的原因，强调了前列腺癌的管理 ERPC 是一项未满足且紧迫的医疗需求。针对 ERPC 的有效疗法的开发进展缓慢由于缺乏对有效杀死 ERPC 细胞的关键分子靶标的正确理解。识别潜在的新目标，我们开发了一种 ERPC 模型，该模型模拟接受治疗的患者的临床状况标准恩杂鲁胺治疗。我们用恩杂鲁胺长期治疗雄激素敏感的前列腺癌细胞长期培养以产生对临床相关不再敏感的细胞系（LNCaP-ENR、PCa-2B-ENR）恩杂鲁胺的剂量。综合基因表达分析显示 ERPC 细胞过度表达 Tribbles 2 (Trib2)，tribbles 假激酶家族的成员。在 PDX 中也发现了 Trib2 的过度表达以及恩杂鲁胺治疗后的前列腺肿瘤患者。强制过度表达 Trib2 导致增强前列腺癌细胞生长和对恩杂鲁胺、阿帕鲁胺、达洛鲁胺和阿比特龙的耐药性。 Trib2 的抑制使耐药细胞对恩杂鲁胺重新敏感并降低其活力，这表明可能 Trib2 与恩杂鲁胺耐药性发展之间的直接联系。有趣的是，Trib2 下调 Rb1 和 p53，同时诱导神经元转录因子（N-Myc、BRN2）和神经内分泌 (NE) 标记物（嗜铬蛋白 A、神经元特异性烯醇化酶和突触素）。抑制 N-Myc 或 BRN2 重新致敏对恩杂鲁胺耐药的细胞。这些发现表明 Trib2 驱动细胞从管腔转分化 NE表型对抗雄激素产生抗性。因此，Trib2 成为一种新型的、有前途的分子 ERPC-NE的治疗靶点。然而，Trib2在NE分化中的机制和作用需要进一步了解。使用适当的体外和体内模型确定。因此，本提案的设计将描述 Trib2 如何诱导 NE 分化（目标 1），确定 Trib2 抑制对增强 ERPC肿瘤生长和远处转移（目标2），并测试Trib2基因靶向对前列腺的影响使用转基因 Trib2 敲除小鼠模型观察肿瘤进展和 NE 分化（目标 3）。成就这些目标将使 Trib2 成为治疗诱导 NE 分化的分子驱动因素，并将有助于开发一种新的靶向治疗策略，用于治疗恩杂鲁胺耐药的 NE 型致死性前列腺癌。