Molecular Mechanisms of Castration Resistant Prostate Cancer Recurrence & Therapeutic Strategies

去势抵抗性前列腺癌复发的分子机制

基本信息

批准号：
10304164
负责人：
Felix Yi-Chung Feng
金额：
$ 59.86万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-12-14 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10304164
关键词：
ACK1 Gene ADME Study Ablation Acetylation Androgen Receptor Androgens Antiandrogen Therapy Biological Markers Biological Models Cell Line Cells Cessation of life Clinic Clinical Data Deposition Development Disease Dose Drug or chemical Tissue Distribution Drug resistance Environment Epigenetic Process Event Exhibits Feedback Formulation Generations Genetic Genetic Transcription Goals Growth Histone H4 Human Introns Malignant neoplasm of prostate Maximum Tolerated Dose Mediator of activation protein Messenger RNA Metastatic Prostate Cancer Modeling Molecular Mus Organoids Outcome Patients Pharmacologic Substance Phosphorylation Phosphotransferases Property Prostate Prostate Cancer therapy RNA Splicing Receptor Signaling Recurrence Research Personnel Resistance Resistance development Role Route Sampling Schedule Signal Transduction Site Stains Stress Therapeutic Therapeutic Studies Time Tissue Microarray Toxicology Transcriptional Activation Treatment Efficacy Up-Regulation Variant Vertebral column Xenograft procedure abiraterone analog androgen deprivation therapy antagonist base cancer recurrence castration resistant prostate cancer clinically significant cohort deprivation drug development enzalutamide high risk histone modification in vivo inhibitor mRNA Expression novel overexpression patient derived xenograft model pre-clinical programs prostate cancer model prostate cancer progression prostate cancer risk receptor receptor binding receptor expression recruit screening small molecule inhibitor standard of care therapeutic target therapy resistant tumor growth

项目摘要

Therapies directed against the androgen receptor (AR) signaling axis represent the backbone of treatment for patients with metastatic prostate cancer, and death from prostate cancer most frequently occurs following the development of resistance to first- or second-line of AR antagonists that includes Enzalutamide and abiraterone. We have uncovered that in androgen- deficient environment or antagonist (e.g. enzalutamide)-rich condition, AR recruits a non- receptor tyrosine kinase, ACK1 (also known as TNK2), which deposits novel pY88-H4 epigenetic marks in the AR locus, facilitating AR and its splice variant, AR-V7 transcription. Significantly, immunohistochemical staining revealed that not only AR expression is upregulated as disease progress to CRPC stage, but also exhibited ACK1 upregulation. However, how ACK1 is up-regulated in CRPCs is not fully clear. In our quest to understand mechanistic details for CRPC recurrence, we observed that enzalutamide-resistant CRPCs exhibit AR acetylation at previously unknown site, Lys609 (ac609-AR). Further, ac609-AR bound to intron 1 of ACK1 gene (at ARBA1 site), upregulating its transcription in androgen-independent manner. These data reveal a previously unknown ACK1/acK609-AR/ACK1 feed-forward signaling loop that promotes CRPC recurrence. These data provided impetus to pursue development of ACK1 inhibitor, (R)-9bMS, which not only mitigated AR/AR-V7 and subsequently ACK1 mRNA expression, but also overcame enzalutamide resistance. Taken together these data suggests that (R)-9bMS with optimal pharmaceutical properties could emerge to be the `third generation' of inhibitors for CRPC treatment. The overall objective of this proposal is to examine the role of ACK1/acK609-AR/ACK1 signaling loop in CRPC recurrence and to perform drug development, biomarker, and preclinical therapeutic studies necessary to credential (R)-9bMS and its potent derivative SG4-176 as a treatment approach, with the long-term goal of ultimately advancing this therapy to the clinic. Specifically we will: Aim 1: Examine the ACK1/acK609-AR/ACK1 signaling loop as a mediator of CRPC progression and a therapeutic target. Aim 2: Investigate ACK1 & ac609-AR status as a biomarker of resistance to enzalutamide and abiraterone. Aim 3: Establish efficacy of (R)-9bMS & SG4-176 in vivo and perform toxicological studies.

针对雄激素受体 (AR) 信号轴的疗法代表了转移性前列腺癌患者的治疗和前列腺癌死亡人数最多经常发生在对一线或二线 AR 产生耐药性后拮抗剂包括恩杂鲁胺和阿比特龙。我们发现，在雄激素中缺乏环境或拮抗剂（例如恩杂鲁胺）丰富的条件下，AR招募非受体酪氨酸激酶 ACK1（也称为 TNK2），可沉积新型 pY88-H4 AR 基因座中的表观遗传标记，促进 AR 及其剪接变体 AR-V7 转录。值得注意的是，免疫组织化学染色显示，不仅 AR 表达上调随着疾病进展到 CRPC 阶段，还表现出 ACK1 上调。然而，如何 ACK1 在 CRPC 中上调尚不完全清楚。在我们寻求了解 CRPC 复发机制细节的过程中，我们观察到恩杂鲁胺耐药的 CRPC 在以前未知的位点 Lys609 处表现出 AR 乙酰化（ac609-AR）。此外，ac609-AR 与 ACK1 基因的内含子 1（ARBA1 位点）结合，上调它以不依赖雄激素的方式转录。这些数据揭示了一个以前未知的促进 CRPC 复发的 ACK1/acK609-AR/ACK1 前馈信号环路。这些数据提供了继续开发 ACK1 抑制剂 (R)-9bMS 的动力，该抑制剂不仅减轻了 AR/AR-V7 和随后的 ACK1 mRNA 表达，但也克服了恩杂鲁胺耐药性。综合这些数据表明 (R)-9bMS 具有最佳药物特性可能成为 CRPC 的“第三代”抑制剂治疗。该提案的总体目标是检查 ACK1/acK609-AR/ACK1 信令的作用 CRPC 复发中的循环并进行药物开发、生物标志物和临床前研究证明 (R)-9bMS 及其有效衍生物 SG4-176 作为治疗药物所必需的治疗研究治疗方法，长期目标是最终将这种疗法推向临床。具体来说，我们将：目标 1：检查 ACK1/acK609-AR/ACK1 信号环路作为 CRPC 进展的中介因素和治疗目标。目标 2：研究 ACK1 和 ac609-AR 状态作为恩杂鲁胺耐药性的生物标志物阿比特龙。目标 3：确定 (R)-9bMS 和 SG4-176 的体内功效并进行毒理学研究。