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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：
10418723
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/10418723
关键词：
ASCL1 gene Adenocarcinoma Androgen Antagonists Androgen Receptor Androgens Antiandrogen Therapy Biology Cell Lineage Cells Clinical Clinical Management Complex Cyclic AMP-Dependent Protein Kinases Data Development Drug resistance Enzymes Epigenetic Process Epithelial Eukaryota Excess Mortality Genetic Genus Tagetes 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 Pharmacology 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 base 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 neuroendocrine differentiation novel prevent programs prostate cancer cell prostate cancer progression protein kinase inhibitor receptor expression receptor function relating to nervous system resistance mechanism response ribosome profiling targeted treatment therapeutic target therapy resistant transcription factor transcriptome 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.

项目总结/文摘