EPHB4 Receptor Kinase as a Target in Prostate Cancer

EPHB4 受体激酶作为前列腺癌的靶点

• 批准号: 8932478
• 负责人: Sarki A. Abdulkadir
• 金额: $ 27.49万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-18 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8932478
• 关键词: 1-Phosphatidylinositol 3-Kinase; Androgen Antagonists; Androgen Receptor; Androgens; Apoptosis; Cancer Patient; Castration; Cell Survival; Cessation of life; Chimeric Proteins; Clinical; Clinical Research; Clinical Trials; Complex; Data; Development; Disease; Disease Progression; Dose-Limiting; Eph Family Receptors; EphB4 Receptor; Ephrin-B2; Epidermal Growth Factor Receptor; Generations; Genes; Genetic; Gleason Grade for Prostate Cancer; Human; IGF1R gene; Knockout Mice; Lead; Ligands; MAP Kinase Gene; Malignant Neoplasms; Malignant neoplasm of prostate; Modality; Modeling; Molecular; Mus; Mutation; Neoplasm Metastasis; Oncogenes; PI3K/AKT; PTEN gene; Pathway interactions; Patients; Phosphotransferases; Play; Pre-Clinical Model; Prostate; Prostatic Neoplasms; Protein Tyrosine Kinase; Proto-Oncogene Proteins c-akt; Receptor Protein-Tyrosine Kinases; Recurrence; Refractory; Relapse; Resistance; Role; Safety; Sampling; Serum Albumin; Signal Pathway; Signal Transduction; TP53 gene; Testing; Therapeutic; Time; Toxic effect; Transgenic Mice; Transgenic Organisms; Translations; Treatment Efficacy; Tumor Suppressor Proteins; Xenograft Model; Xenograft procedure; abiraterone; abstracting; angiogenesis; cancer recurrence; castration resistant prostate cancer; cell motility; clinically relevant; cohort; deprivation; high risk; inhibitor/antagonist; men; mouse model; neoplastic cell; new therapeutic target; novel; novel therapeutic intervention; novel therapeutics; overexpression; phase 1 study; phase II trial; pre-clinical; prostate cancer cell; prostate cancer model; prostate carcinogenesis; receptor; receptor expression; resistance mechanism; targeted treatment; therapeutic target; therapy development; therapy resistant; tumor; tumor progression; tumor xenograft

PROJECT 3: PROJECT SUMMARY/ABSTRACT A major clinical problem in the management of prostate cancer is the difficulty associated with treating aggressive cancers, especially those that are highly castration resistant. The androgen signaling pathway remains a key therapeutic target for advanced prostate cancer but resistance to agents targeting this pathway is common, highlighting the need to develop novel therapeutic approaches. Mouse prostate cancer modeling has elucidated molecular pathways of aggressive, castration-resistant prostate cancer (CRPC) which include loss of the tumor suppressors PTEN and TP53 and overexpression of the MYC oncogene. Using these spontaneous mouse models of prostate cancer we have identified Ephrin receptor EphB4 as a potential therapeutic target. EPHB4 is a receptor tyrosine kinase that with its ligand ephrin B2, are not expressed in normal prostate gland, but are expressed in a majority of human prostate cancers. EPHB4 is induced by multiple pathways important for CRPC development, including loss of PTEN and TP53 as well as activation of the PI3K pathway downstream of EGFR and IGF1R. In turn, EPHB4 activation engages multiple signaling pathways, including the PI3 kinase/AKT and MAPK pathways known to modulate the androgen receptor and drive CRPC development. To test the significance of EphB4, we generated conditional EphB4 knockout mouse. We found that genetic deletion of EphB4 or its inhibition using a soluble antagonist (sEPHB4) profoundly inhibited prostate tumorigenesis driven by loss of Pten and led to the regression of established tumors in transgenic mice. This was associated with inhibition of PI3K/AKT signaling and apoptosis. Notably, sEpBh4 antagonist and EphB4 knockdown led to markedly lower levels of androgen receptor (AR) protein. These functional genetic data lead us to hypothesize that EPHB4 is a novel pharmacologic target with high therapeutic potential in prostate cancer, including CRPC. We will explore this hypothesis by targeting EphB4 in genetically complex mouse models (loss of Pten, Tp53 and Myc over-expression) and human xenograft models of prostate cancer and CRPC, singly or in combination with AR-targeted therapy (including enzalutamide, abiraterone). We will examine human prostate tumor samples including metastases and CRPCs for the expression of EphB4, EphrinB2, and downstream markers. A soluble decoy EPHB4 receptor – human serum albumin fusion protein (sEPHB4HSA) antagonist is in early human trials in other tumors, and has been found to be remarkably safe in Phase I study. We will therefore implement a feasibility clinical trial of sEPHB4HSA aimed at determining the therapeutic efficacy of targeting EPHB4 in men with CRPC. Successful completion of the preclinical and early clinical studies we propose in this application could lead to a rapid translation of soluble EPHB4 antagonist as a treatment for advanced prostate cancer.

项目 3：项目摘要/摘要 前列腺癌治疗中的一个主要临床问题是难以进行积极的治疗 癌症，尤其是那些高度去势抵抗的癌症。雄激素信号通路仍然是关键 晚期前列腺癌的治疗靶点，但针对该途径的药物耐药性很常见， 强调需要开发新的治疗方法。小鼠前列腺癌模型已阐明 侵袭性去势抵抗性前列腺癌 (CRPC) 的分子途径，包括肿瘤的消失 抑制因子 PTEN 和 TP53 以及 MYC 癌基因的过度表达。使用这些自发的鼠标 在前列腺癌模型中，我们已将 Ephrin 受体 EphB4 确定为潜在的治疗靶点。 EPHB4是 一种受体酪氨酸激酶，其配体肝配蛋白 B2 在正常前列腺中不表达，但在 在大多数人类前列腺癌中表达。 EPHB4 由对 CRPC 重要的多种途径诱导 发育，包括 PTEN 和 TP53 的丢失以及 EGFR 下游 PI3K 通路的激活 和 IGF1R。反过来，EPHB4 激活涉及多种信号传导途径，包括 PI3 激酶/AKT 和 MAPK 通路已知可调节雄激素受体并驱动 CRPC 发展。测试 为了研究EphB4的意义，我们制备了条件性EphB4基因敲除小鼠。我们发现基因缺失 EphB4 或其使用可溶性拮抗剂 (sEPHB4) 的抑制可深度抑制前列腺肿瘤发生 Pten 的缺失导致转基因小鼠体内已形成的肿瘤消退。这与 抑制 PI3K/AKT 信号传导和细胞凋亡。值得注意的是，sEpBh4 拮抗剂和 EphB4 敲低导致 雄激素受体（AR）蛋白水平显着降低。这些功能性遗传数据使我们做出假设 EPHB4 是一种新的药理学靶点，对前列腺癌（包括 CRPC）具有很高的治疗潜力。 我们将通过在遗传复杂的小鼠模型中靶向 EphB4（Pten、Tp53 缺失）来探索这一假设。 和 Myc 过表达）以及前列腺癌和 CRPC 的人类异种移植模型，单独或组合 AR靶向治疗（包括恩杂鲁胺、阿比特龙）。我们将检查人类前列腺肿瘤样本 包括表达 EphB4、EphrinB2 和下游标记的转移灶和 CRPC。一种可溶性 诱饵 EPHB4 受体 - 人血清白蛋白融合蛋白 (sEPHB4HSA) 拮抗剂正在进行早期人体试验 在其他肿瘤中，并且在 I 期研究中发现非常安全。因此，我们将实施一项 sEPHB4HSA 的可行性临床试验旨在确定针对男性 EPHB4 的治疗效果 与 CRPC。成功完成我们在本申请中提出的临床前和早期临床研究 可能导致可溶性 EPHB4 拮抗剂快速转化为晚期前列腺癌的治疗方法。