Targeting m6A RNA epigenetics in treatment-emergent neuroendocrine prostate cancer

靶向 m6A RNA 表观遗传学治疗神经内分泌前列腺癌

基本信息

批准号：
10652423
负责人：
Min Sup Song
金额：
$ 36.32万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-04 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10652423
关键词：
ASCL1 gene Adenocarcinoma Androgen Antagonists Androgen Receptor Androgens Antiandrogen Therapy Biology Cell Fate Control Cell Lineage Cells Clinical Clinical Management Complex Cyclic AMP-Dependent Protein Kinases Data Development Drug resistance Enzymes Epigenetic Process Epithelium Eukaryota Excess Mortality Genetic Goals Heterogeneity Histologic In Vitro Knowledge Laboratories Link Malignant Neoplasms Malignant neoplasm of prostate Mediating Medical Messenger RNA Methyltransferase Mission Modification Molecular Mus Neoplasm Metastasis Neuroendocrine Prostate Cancer Neurosecretory Systems Outcome Pathologic Pathway interactions Patient Care Patient Selection Patient-Focused Outcomes Patients Phenotype Post-Transcriptional Regulation Process Prostate Cancer therapy Protein Kinase A Inhibitor Public Health Quality of life RNA Receptor Signaling Recurrence Research Resistance Role Testing Therapeutic Therapeutic Intervention Tissues Translating Translations United States National Institutes of Health Variant Work bioprocess cancer cell cancer drug resistance cancer therapy cancer type castration resistant prostate cancer clinical application combat epitranscriptome genetic analysis improved improved outcome in vivo Model inhibitor neural neuroendocrine differentiation novel pharmacologic prevent programs prostate cancer cell prostate cancer progression protein kinase inhibitor receptor expression receptor function resistance mechanism response ribosome profiling targeted treatment therapeutic target therapy resistant transcription factor transcriptomic profiling transdifferentiation tumor

项目摘要

Project Summary/Abstract Castration-resistant prostate cancer is associated with substantial clinical, pathologic, and molecular heterogeneity; most tumors remain driven by androgen receptor (AR) signaling, which has clinical implications for patient selection for AR-directed therapies. However, histologic and clinical resistance phenotypes can also emerge after prolonged AR pathway inhibition, in which the tumors become less dependent on AR signaling (referred to as ‘androgen indifferent’). These highly aggressive and lethal tumors, termed treatment-emergent neuroendocrine prostate cancer (t-NEPC), are clonally derived from adenocarcinoma through lineage plasticity or transdifferentiation. There is an urgent need for novel targets and therapies for t-NEPC. t-NEPC cells carry recurrent genetic and epigenetic alterations as an adaptive response, thus suggesting that key molecular pathways and drivers controlling cell fate may be used as targets for therapeutic intervention. N6- methyladenosine (m6A) is an abundant internal RNA modification in eukaryote messenger RNAs. Despite its functional importance in different types of cancer, their specific role in prostate cancer progression and therapy resistance still remains elusive. Our integrative analysis of phosphoproteome, epitranscriptome, transcriptome, and ribosome profiling using in vitro and in vivo models identified m6A as exciting new epigenetic mark underlying prostate cancer lineage transition and therapeutic resistance. We therefore hypothesize that m6A drives lineage plasticity and is dynamically regulated by antiandrogen in prostate cancer, and that targeting m6A can reverse the lineage transformation, thereby restoring sensitivity to antiandrogen therapy in t-NEPC. We will test our central hypothesis by pursuing the following specific aims: (1) Determine the functional significance of m6A RNA epigenetics for therapeutic resistance in prostate cancer; (2) Elucidate the molecular mechanisms of m6A function in prostate cancer lineage plasticity and antiandrogen resistance; and (3) Establish the therapeutic potential of inhibitors tageting m6A for treatment of t-NEPC. The outcomes of this project are expected to open new avenues for t-NEPC therapeutics in linking m6A RNA epigenetics to lineage plasticity-mediated therapy resistance, and should have a profound impact on our approach to tackle the greatest challenges facing patients with treatment-emergent maligancies.

项目概要/摘要去势抵抗性前列腺癌与大量的临床、病理和分子水平相关。异质性；大多数肿瘤仍然由雄激素受体（AR）信号驱动，这具有临床意义然而，组织学和临床耐药表型也可能会影响患者的选择。长期抑制 AR 通路后出现，其中肿瘤对 AR 信号传导的依赖程度降低（称为“雄激素无关”）这些高度侵袭性和致命性的肿瘤，被称为治疗引起的肿瘤。神经内分泌前列腺癌（t-NEPC）是通过谱系可塑性从腺癌克隆衍生而来 t-NEPC 细胞迫切需要新的靶点和治疗方法。反复发生的遗传和表观遗传改变是一种适应性反应，因此表明关键分子控制细胞命运的途径和驱动因素可用作治疗干预的目标。甲基腺苷 (m6A) 是真核生物信使 RNA 中丰富的内部 RNA 修饰。在不同类型癌症中的功能重要性及其在前列腺癌进展和治疗中的具体作用我们对磷酸化蛋白质组、表观转录组、转录组的综合分析仍然难以捉摸。使用体外和体内模型的核糖体分析将 m6A 确定为令人兴奋的新表观遗传标记因此，我们研究了潜在的前列腺癌谱系转变和治疗耐药性。驱动谱系可塑性，并受到前列腺癌中抗雄激素的动态调节，并且靶向 m6A 可以逆转谱系转化，从而恢复 t-NEPC 对抗雄激素治疗的敏感性。我们将通过追求以下具体目标来检验我们的中心假设：（1）确定函数 m6A RNA 表观遗传学对前列腺癌治疗耐药的意义 (2) 阐明分子机制； m6A 在前列腺癌谱系可塑性和抗雄激素抵抗中的作用机制；以及 (3) 确定 m6A 抑制剂治疗 t-NEPC 的治疗潜力。该项目预计将为 t-NEPC 疗法开辟新途径，将 m6A RNA 表观遗传学与谱系联系起来可塑性介导的治疗耐药性，应该对我们解决这一问题的方法产生深远的影响治疗中出现的恶性肿瘤患者面临的最大挑战。