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

• 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
• 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

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.

抗雄激素疗法是前列腺癌的原发性和传播形式的主要支柱。 fda- 批准的enzalutamide（XTANDI）处于具有较高患者概况的抗雄激素的最前沿，这是一个 大多数处方。然而，enzalutamide耐药前列腺癌（ERPC）总是发展出来，这是 无法治愈并负责大多数与癌症相关的死亡，强调了 ERPC是未满足和紧急的医疗需求。开发针对ERPC的有效疗法正在受苦 由于缺乏对关键分子靶标的正确理解，可以有效杀死ERPC细胞。识别 潜在的新目标，我们开发了一个ERPC模型，该模型模仿正在接受的患者的临床状况 标准的恩扎拉酰胺治疗。我们在长长的 产生细胞系（LNCAP-ENR，PCA-2B-ENR）的术语培养，不再对临床相关敏感 enzalutamide剂量。全面的基因表达分析表明，ERPC细胞过表达 Tribbles 2（Trib2），Tribbles假发酶家族的成员。在PDX中也发现了Trib2的过表达 恩扎拉酰胺治疗后的患者前列腺肿瘤。强迫过表达Trib2导致增强 前列腺癌细胞的生长和对恩扎拉酰胺，阿apalutamide，darolutamide和abiraterone的耐药性。 抑制Trib2将抗性细胞重新敏感以使乙酰氨酰胺并降低其生存力，表明可能 Trib2与enzalutamide抗性的发展之间的直接联系。有趣的是，Trib2下调RB1 和p53，而诱导神经元转录因子（N-MYC，BRN2）和神经内分泌（NE）标记 （染色体蛋白A，神经元特异性烯醇酶和突触素）。抑制N-MYC或BRN2重新敏感 抗性细胞对enzalutamide。这些发现表明，Trib2从腔中驱动细胞反差异 向NE表型带来对抗雄激素的抗性。因此，Trib2是一种新颖的，有希望的分子 ERPC-NE治疗的靶标。但是，Trib2在NE区分中的机制和作用需要是 使用适当的体外和体内模型确定。因此，该建议的设计将 表征了Trib2如何诱导NE分化（AIM 1），确定Trib2抑制在增强中的影响 ERPC肿瘤生长和远处转移（AIM 2），并测试靶向前列腺的影响 使用转基因部落2基因敲除小鼠模型的肿瘤进展和NE分化（AIM 3）。完成 这些目标将建立部落2作为治疗引起的NE分化的分子驱动器，并将有助于 制定一种新的靶向治疗策略，以抗enzalutamide抗性，NE型，致命的前列腺癌。