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.

项目概要前列腺癌是美国男性癌症死亡的第二大常见原因。早期前列腺癌通常对激素治疗有反应，其中一部分会发展为无法治愈的“去势- 抵抗”状态（CRPC），对标准激素疗法具有抵抗力，这是 CRPC 的一个决定性分子特征。是雄激素受体 (AR) 信号传导的重新激活，表明 AR 仍然是前列腺癌的核心因此，消除 AR 信号传导的新方法可以激发新的治疗方法。通过基因组规模的 CRISPR/Cas9 筛选，我们鉴定出了精氨酸蛋白。甲基转移酶 1 和 5 (PRMT1/PRMT5) 作为 AR 途径的新型调节剂。通过翻译后修饰调节多种生物过程，包括 AR 信号传导精氨酸残基上的底物蛋白最近已成为 PRMT1 和 PRMT5 的小分子抑制剂。进入临床开发后，该途径也可以在患者中进行治疗调节。该提案检验了 PRMT 可能在调节 AR 驱动的转录中具有特定作用的假设通过直接影响 AR 和/或其辅助因子的方案，以及与 PRMT 抑制剂的联合治疗在目标 1 中，直接 AR 拮抗剂可能是晚期前列腺癌的有效治疗策略。我们将剖析 PRMT1 和 PRMT5 调节 AR 信号传导的分子机制。然后我们将比较 PRMT1 和 PRMT5 对各种细胞环境中 AR 信号传导的影响。研究这些 PRMT 在调节各个节点 AR 信号传导中的作用，包括组蛋白修饰，在目标 2 中，我们将研究染色质结构、AR 协同调节因子的修饰以及 AR 本身的修饰。确定 PRMT1 和/或 PRMT5 抑制剂与 AR 拮抗剂组合的治疗潜力由于我们的初步数据表明 PRMT1 和 PRMT5 均具有体外和体内前列腺癌模型。调节 AR 信号转导，我们追求将抑制这两种酶与直接抑制 AR 相结合可能是治疗去势抵抗性前列腺癌并延缓去势发生的有效策略此外，先前的研究表明PRMT1和PRMT5的组合具有协同作用。因此，我们将在临床前体内模型中测试直接 AR 拮抗剂的活性。在体内患者来源的激素异种移植模型中与 PRMT1 和/或 PRMT5 抑制剂联合使用最后，我们将探究 PRMT1 与去势抵抗性前列腺癌之间的关系。 PRMT5 和 AR 在临床注释的前列腺癌组织标本和大规模前列腺中的表达癌症测序数据集。这些实验将验证 PRMT1 和 PRMT5 作为前列腺癌的治疗靶点，并将有助于总体而言，这项工作推进了机制驱动的机制。假设有可能改善晚期前列腺癌患者的治疗结果。