Regulation of androgen receptor signaling in prostate cancer by protein arginine methylation

通过蛋白质精氨酸甲基化调节前列腺癌中的雄激素受体信号传导

基本信息

批准号：
10584689
负责人：
Srinivas Raghavan Viswanathan
金额：
$ 58.98万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-01 至 2028-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10584689
关键词：
Ablation Affect Androgen Receptor Architecture Arginine Automobile Driving Binding Biological Process CRISPR screen Cancer Etiology Castration Cause of Death Cell Line Cells Cessation of life Chromatin Clinical Combined Modality Therapy Complex Data Data Set Disease Disease Progression Enhancers Enzymes Epigenetic Process Genetic Screening Genetic Transcription Genomics Goals Hormone Receptor Hormones In Vitro Knock-in Malignant neoplasm of prostate Mediating Methylation Modeling Modification Molecular Output Pathogenesis Pathway interactions Patient-Focused Outcomes Patients Phase Post-Translational Protein Processing Protein-Arginine N-Methyltransferase Proteins Receptor Signaling Regulation Reporter Resistance Resistance development Role Site Specimen Testing Therapeutic Tissues Treatment Efficacy United States Work advanced prostate cancer androgen deprivation therapy antagonist castration resistant prostate cancer clinical development cofactor curative treatments experimental study genetic corepressor genome-wide histone modification hormone therapy human disease improved outcome in vivo in vivo Model inhibitor insight men next generation novel novel strategies novel therapeutic intervention patient derived xenograft model posttranscriptional pre-clinical programs prostate cancer model receptor receptor expression small molecule inhibitor therapeutic target therapeutically effective

项目摘要

PROJECT SUMMARY Prostate cancer is the second most common cause of cancer death among men in the United States. While early-stage prostate cancers often respond to hormonal therapy, a subset progresses to an incurable “castration- resistant” state (CRPC), which is resistant to standard hormonal therapies. A defining molecular feature of CRPC is the reactivation of androgen receptor (AR) signaling, indicating that the AR remains central to prostate cancer pathogenesis across disease states. Therefore, novel means of ablating AR signaling can inspire new treatment strategies for CRPC. Through a genome-scale CRISPR/Cas9 screen, we identified the protein arginine methyltransferases 1 and 5 (PRMT1/PRMT5) as novel regulators of the AR pathway. Both PRMT1 and PRMT5 modulate diverse biological processes, including AR signaling, through post-translational modification of substrate proteins on arginine residues. As small molecule inhibitors of PRMT1 and PRMT5 have recently entered clinical development, this pathway can also be therapeutically modulated in patients. This proposal tests the hypothesis that PRMTs may have a specific role in regulating AR-driven transcriptional programs through direct effects on AR and/or its co-factors, and that combination therapy with PRMT inhibitors and direct AR antagonists may be an effective therapeutic strategy in advanced prostate cancer. In Aim 1, we will dissect the molecular mechanisms by which PRMT1 and PRMT5 regulate AR signaling. Specifically, we will compare the effects that PRMT1 and PRMT5 have on AR signaling in various cellular contexts. We will then investigate roles for these PRMTs in modulating AR signaling at various nodes, including histone modification, chromatin architecture, modification of AR co-regulators, and modification of the AR itself. In Aim 2, we will establish the therapeutic potential of combining PRMT1 and/or PRMT5 inhibitors with an AR antagonist in in vitro and in vivo prostate cancer models. Since our preliminary data indicate that both PRMT1 and PRMT5 modulate AR signaling, we hypothesize that inhibiting both enzymes in combination with direct inhibition of AR may be an effective strategy to treat castration-resistant prostate cancer and to delay the emergence of castration resistance. Moreover, prior studies have shown that the combination of PRMT1 and PRMT5 is synergistic and well-tolerated in preclinical in vivo models. We will therefore test the activity of direct AR antagonists in combination with PRMT1 and/or PRMT5 inhibitors in in vivo patient-derived xenograft models of hormone- sensitive and castration-resistant prostate cancer. Finally, we will interrogate the relationship between PRMT1, PRMT5, and AR expression in clinically-annotated prostate cancer tissue specimens and in large-scale prostate cancer sequencing datasets. These experiments will validate PRMT1 and PRMT5 as therapeutic targets in prostate cancer and will lend insight into the mechanisms by which AR signaling is regulated. Overall, this work advances a mechanism-driven therapeutic hypothesis with the potential to improve outcomes for patients with advanced prostate cancer.

项目摘要前列腺癌是美国男性癌症死亡的第二大最常见原因。尽管早期前列腺癌经常对荷尔蒙治疗作出反应，一个子集发展为无法治愈的“ cast割 - 抗性”状态（CRPC），对标准激素疗法具有抗性。CRPC的定义分子特征是雄激素受体（AR）信号传导的重新激活，表明AR仍然是前列腺癌的中心跨疾病状态的发病机理。因此，新颖的消除AR信号的方法可以激发新的治疗 CRPC的策略。通过基因组规模的CRISPR/CAS9屏幕，我们确定了蛋白质精氨酸甲基转移酶1和5（PRMT1/PRMT5）作为AR途径的新调节剂。 PRMT1和PRMT5都通过翻译后修饰调节潜水员的生物学过程，包括AR信号传导精氨酸残留物上的底物蛋白。由于PRMT1和PRMT5的小分子抑制剂最近具有进入临床发育，该途径也可以在患者中进行热调节。该提案检验了以下假设，即PRMT可能在调节AR驱动的转录中具有特定作用通过直接影响AR和/或其共同因素的计划，并与PRMT抑制剂组合疗法直接AR拮抗剂可能是晚期前列腺癌的有效治疗策略。在AIM 1中，我们将阐述PRMT1和PRMT5调节AR信号传导的分子机制。具体来说，我们会的比较PRMT1和PRMT5对各种细胞环境中AR信号传导的影响。然后我们会研究这些PRMT在调节各种节点的AR信号传导中的作用，包括Hisstone修饰，染色质体系结构，AR共同调节器的修改以及AR本身的修改。在AIM 2中，我们将建立将PRMT1和/或PRMT5抑制剂与AR拮抗剂组合的治疗潜力体外和体内前列腺癌模型。由于我们的初步数据表明PRMT1和PRMT5既调节AR信号传导，我们假设抑制两种酶与直接抑制AR结合可能是治疗耐cast割前列腺癌并延迟cast割出现的有效策略反抗。此外，先前的研究表明，PRMT1和PRMT5的组合是协同的，并且在临床前体内模型中耐受性良好。因此，我们将测试直接AR拮抗剂在与PRMT1和/或PRMT5抑制剂结合在体内患者衍生的马酮的异种移植模型敏感和cast割的前列腺癌。最后，我们将询问prmt1之间的关系 PRMT5和AR表达在临床上注销的前列腺癌组织和大规模前列腺中癌症测序数据集。这些实验将验证PRMT1和PRMT5作为前列腺癌的治疗靶标，并将借出洞悉调节AR信号的机制。总体而言，这项工作推进了机构驱动的治疗假设有可能改善晚期前列腺癌患者的预后。