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

• 批准号: 10523108
• 负责人: Felix Yi-Chung Feng
• 金额: $ 65.19万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 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/10523108
• 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; Credentialing; Data; Deposition; Development; Disease Progression; 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; Messenger RNA; Metastatic Prostate Cancer; Modeling; Molecular; Mus; Organoids; Outcome; Patients; Pharmacologic Substance; Phosphorylation; Phosphotransferases; Property; Prostate; Prostate Cancer therapy; Protein Tyrosine Kinase; RNA Splicing; Receptor Signaling; Recurrence; Recurrent Malignant Neoplasm; 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; cancer recurrence; castration resistant prostate cancer; clinically significant; cohort; deprivation; drug development; efficacy evaluation; 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

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）信号传导轴的治疗代表了雄激素治疗的支柱。 治疗转移性前列腺癌患者，以及大多数前列腺癌患者的死亡率 经常发生在对一线或二线AR产生耐药性后 拮抗剂，包括Enzalutamide和阿比特龙。我们发现在雄激素中- 缺乏环境或拮抗剂（如恩杂鲁胺）丰富的条件下，AR招募非- 受体酪氨酸激酶，ACK 1（也称为TNK 2），其沉积新的pY 88-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，但也表现出ACK 1上调。但如何 ACK 1在CRPC中的上调尚不完全清楚。 在我们寻求了解CRPC复发的机制细节时，我们观察到， Enzalutamide耐药CRPC在以前未知的位点Lys 609表现出AR乙酰化 （ac609-AR）。此外，ac 609-AR与ACK 1基因的内含子1结合（在ARBA 1位点），上调了 其转录以雄激素非依赖性方式进行。这些数据揭示了一种以前未知的 ACK 1/acK 609-AR/ACK 1前馈信号循环，促进CRPC复发。这些 这些数据为开发ACK 1抑制剂（R）-9bMS提供了动力， 减轻AR/AR-V7和随后的ACK 1 mRNA表达，但也克服了 恩杂鲁胺耐药。总之，这些数据表明，具有最佳的（R）-9bMS 药物特性可能成为CRPC的“第三代”抑制剂 治疗 该提议的总体目标是检查ACK 1/acK 609-AR/ACK 1信令的作用 循环CRPC复发，并进行药物开发，生物标志物和临床前 证明（R）-9bMS及其有效衍生物SG 4 -176作为一种有效的抗肿瘤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。 具体而言，我们将： 目的1：检查ACK 1/acK 609-AR/ACK 1信号环作为CRPC进展的介质 和治疗靶点。 目的2：研究ACK 1和ac 609-AR状态作为恩杂鲁胺抗性的生物标志物， 阿比特龙 目的3：确定（R）-9bMS和SG 4 -176在体内的功效并进行毒理学研究。

项目成果

An integrated functional and clinical genomics approach reveals genes driving aggressive metastatic prostate cancer.

• DOI: 10.1038/s41467-021-24919-7
• 发表时间: 2021-07-29
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Das R;Sjöström M;Shrestha R;Yogodzinski C;Egusa EA;Chesner LN;Chen WS;Chou J;Dang DK;Swinderman JT;Ge A;Hua JT;Kabir S;Quigley DA;Small EJ;Ashworth A;Feng FY;Gilbert LA
• 通讯作者: Gilbert LA

Prostate cancer immunotherapy: Improving clinical outcomes with a multi-pronged approach.

• DOI: 10.1016/j.xcrm.2023.101199
• 发表时间: 2023-10-17
• 期刊: CELL REPORTS MEDICINE
• 影响因子: 14.3
• 作者: Sridaran, Dhivya;Bradshaw, Elliot;Deselm, Carl;Pachynski, Russell;Mahajan, Kiran;Mahajan, Nupam P.
• 通讯作者: Mahajan, Nupam P.

The splicing modulator sulfonamide indisulam reduces AR-V7 in prostate cancer cells.

• DOI: 10.1016/j.bmc.2020.115712
• 发表时间: 2020-08
• 期刊: Bioorganic & medicinal chemistry
• 影响因子: 3.5
• 作者: James E. Melnyk;V. Steri;Hao G Nguyen;B. Hann;F. Feng;K. Shokat

Targeting a splicing-mediated drug resistance mechanism in prostate cancer by inhibiting transcriptional regulation by PKCβ1.

• DOI: 10.1038/s41388-022-02179-z
• 发表时间: 2022-03
• 期刊: Oncogene
• 影响因子: 8
• 作者: Melnyk JE;Steri V;Nguyen HG;Hwang YC;Gordan JD;Hann B;Feng FY;Shokat KM
• 通讯作者: Shokat KM

Inhibiting ACK1-mediated phosphorylation of C-terminal Src kinase counteracts prostate cancer immune checkpoint blockade resistance.

• DOI: 10.1038/s41467-022-34724-5
• 发表时间: 2022-11-14
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Sridaran, Dhivya;Chouhan, Surbhi;Mahajan, Kiran;Renganathan, Arun;Weimholt, Cody;Bhagwat, Shambhavi;Reimers, Melissa;Kim, Eric H.;Thakur, Manish K.;Saeed, Muhammad A.;Pachynski, Russell K.;Seeliger, Markus A.;Miller, W. Todd;Feng, Felix Y.;Mahajan, Nupam P.
• 通讯作者: Mahajan, Nupam P.