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：项目总结/摘要 前列腺癌治疗中的一个主要临床问题是与治疗侵袭性前列腺癌相关的困难。 癌症，特别是那些高度去势抵抗的癌症。雄激素信号通路仍然是 晚期前列腺癌的治疗靶点，但对靶向该途径的药剂的抗性是常见的， 突出了开发新的治疗方法的需要。小鼠前列腺癌模型已经阐明了 侵袭性去势抵抗性前列腺癌（CRPC）的分子途径，包括肿瘤丢失 抑制因子PTEN和TP 53以及MYC癌基因的过表达。用这些自发的老鼠 在前列腺癌模型中，我们已将肝配蛋白受体EphB 4确定为潜在的治疗靶点。EPHB 4是 一种受体酪氨酸激酶，与其配体肝配蛋白B2一起在正常前列腺中不表达，但 在大多数人前列腺癌中表达。EPHB 4由CRPC重要的多个途径诱导 发展，包括PTEN和TP 53的丢失以及EGFR下游PI 3 K途径的激活 IGF1R反过来，EPHB 4激活参与多个信号传导途径，包括PI 3激酶/AKT， 已知MAPK途径可调节雄激素受体并驱动CRPC的发展。测试 为了证实EphB 4的重要性，我们产生了条件性EphB 4敲除小鼠。我们发现， EphB 4或使用可溶性拮抗剂（sEPHB 4）抑制其可显著抑制前列腺肿瘤发生驱动的前列腺肿瘤发生。 通过Pten的丢失，导致转基因小鼠中已建立的肿瘤消退。这是与 抑制PI 3 K/AKT信号传导和细胞凋亡。值得注意的是，sEpBh 4拮抗剂和EphB 4敲低导致了 雄激素受体（AR）蛋白水平显著降低。这些功能基因数据让我们假设 EPHB 4是前列腺癌（包括CRPC）中具有高治疗潜力新药理学靶点。 我们将通过在遗传复杂的小鼠模型中靶向EphB 4（Pten、Tp 53缺失）来探索这一假设。 和Myc过表达）和前列腺癌和CRPC的人异种移植物模型 AR靶向治疗（包括enzalutamide、阿比特龙）。我们将检查人类前列腺肿瘤样本 包括转移瘤和CRPC，用于表达EphB 4、EphrinB 2和下游标志物。可溶性 诱饵EPHB 4受体-人血清白蛋白融合蛋白（sEPHB 4 HSA）拮抗剂处于早期人体试验中 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 sEPHB 4 HSA的可行性临床试验，旨在确定靶向EPHB 4在男性中的治疗效果 在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 可以导致可溶性EPHB 4拮抗剂的快速翻译作为晚期前列腺癌的治疗。