Determining the role of ASCL1 in neuroendocrine prostate cancer

确定 ASCL1 在神经内分泌前列腺癌中的作用

基本信息

批准号：
10313551
负责人：
Kathia E. Rodarte
金额：
$ 3.47万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
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：
2021-07-09 至 2024-07-08
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10313551
关键词：
ASCL1 gene ATAC-seq Androgen Receptor Automobile Driving Basal Cell Biological Biological Assay Biomedical Research CRISPR interference Cancer Biology Cancer Histology Cancer Patient Cell Line Cell Lineage Cell Survival Cells ChIP-seq Chromatin Complex Development Developmental Gene Diagnosis Disease Disease model Distal Engineering Enterobacteria phage P1 Cre recombinase Ethics Experimental Models Exposure to Fellowship Gene Expression Genes Genetic Genetic Transcription Genetically Engineered Mouse Genomic Segment Growth Histologic Human In Vitro Knock-out Knowledge LoxP-flanked allele Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of prostate Modeling Mus Neuroendocrine Cell Neuroendocrine Prostate Cancer Neurosecretory Systems Nucleic Acid Regulatory Sequences Organoids Patients Play Population Pre-Clinical Model Process Prostate Prostate Adenocarcinoma Prostate Cancer therapy RB1 gene Regulation Repression Research Resistance Resistance development Role Sampling TP53 gene Techniques Testing Training Tumor Suppressor Genes Tumor Suppressor Proteins Xenograft procedure androgen deprivation therapy cancer gene expression cancer subtypes cancer therapy castration resistant prostate cancer cell growth cell type experience insight knock-down loss of function lung small cell carcinoma mouse model neoplastic cell neuroendocrine cancer neuroendocrine phenotype novel therapeutic intervention patient derived xenograft model pre-clinical pressure programs prostate cancer cell line prostate cancer model survival outcome transcription factor tumor

项目摘要

Most patients with prostate adenocarcinoma, an androgen receptor (AR) driven cancer, develop castrate resistant prostate cancer (CRPC) due to resistance to first-line androgen deprivation therapies. Consequently, as a second-line therapy, patients are treated with a potent AR antagonist called enzalutamide (Enz). However, a portion of CRPC patients treated with Enz develop neuroendocrine prostate cancer (NEPC), which is a rapidly progressing cancer with limited therapies and poor survival outcomes. Current research to understand the CRPC transition to NEPC suggests a model of lineage plasticity, where the AR-dependent tumors with luminal cell-type features transition through a multi-potential lineage state. Under selection pressure of the therapy, the cells progress towards an AR-independent neuroendocrine lineage. Several groups have found human NEPC tumors have lost RB1 and TP53, and in experimental models, loss of both genes was required for this transition to a neuroendocrine lineage. Notably, NEPC histology and gene expression resemble another neuroendocrine cancer, small cell lung carcinoma (SCLC), a cancer also characterized by loss of RB1 and TP53. In SCLC, the transcription factor ASCL1 is required for tumor cell growth in vitro, and for SCLC formation in a mouse model of this disease. ASCL1 is present in NEPC tumors and in some cell line models of the disease. The current proposal is aimed at determining if ASCL1 is required in the transition of prostate adenocarcinoma to NEPC, and identifying the gene programs regulated by ASCL1 in this process. In addition, mechanisms leading to the elevated levels of ASCL1 with RB1/TP53 loss will be explored. Gain- and loss-of-function approaches of ASCL1 in NEPC cell lines, NEPC patient-derived xenografts, and mouse prostate organoid models from genetically engineered mice will be conducted to determine what role if any ASCL1 plays in this cancer. Comparing ASCL1 function and regulation in NEPC with those in SCLC may reveal common mechanisms and vulnerabilities in these and other neuroendocrine cancers. This fellowship provides training in how to perform scientifically rigorous and ethical biomedical research and how to communicate scientific findings to the field, particularly as it relates to biological mechanisms underlying cancer. The expertise from Dr. Jane Johnson’s lab in developmental transcription factors and neuroendocrine lung cancer, and Dr. Ping Mu’s lab in prostate cancer therapy resistance will provide the necessary knowledge and techniques required for a successful training experience and completion of the proposed project.

大多数患有前列腺癌（一种雄激素受体 (AR) 驱动的癌症）的患者会发展为去势由于对一线雄激素剥夺疗法的耐药性而导致的耐药性前列腺癌（CRPC），作为二线治疗，患者使用一种名为恩杂鲁胺 (Enz) 的强效 AR 拮抗剂进行治疗。部分接受 Enz 治疗的 CRPC 患者会发展为神经内分泌前列腺癌 (NEPC)，这是一种快速进展的疾病目前对 CRPC 的研究表明，治疗方法有限且生存结果不佳。向 NEPC 的过渡提出了一种谱系可塑性模型，其中具有管腔细胞类型的 AR 依赖性肿瘤在治疗的选择压力下，细胞具有通过多潜能谱系状态转变的特征。几个研究小组已经发现了人类 NEPC 肿瘤的研究进展。已经失去了 RB1 和 TP53，并且在实验模型中，需要失去这两个基因才能转变为值得注意的是，NEPC 的组织学和基因表达类似于另一种神经内分泌谱系。癌症，小细胞肺癌 (SCLC)，也是一种以 RB1 和 TP53 缺失为特征的癌症。转录因子 ASCL1 是体外肿瘤细胞生长和小鼠模型中 SCLC 形成所必需的 ASCL1 存在于 NEPC 肿瘤和该疾病的某些细胞系模型中。该提案旨在确定前列腺腺癌向 NEPC 的转变是否需要 ASCL1，以及识别在此过程中受 ASCL1 调节的基因程序。将探索 ASCL1 水平升高且 RB1/TP53 缺失的 ASCL1 功能获得和丧失方法。在 NEPC 细胞系、NEPC 患者来源的异种移植物和来自遗传的小鼠前列腺类器官模型中将用工程小鼠来比较 ASCL1 是否在这种癌症中发挥什么作用。 NEPC 与 SCLC 中的功能和监管可能会揭示 NEPC 中的共同机制和漏洞该奖学金提供如何科学地进行治疗的培训。严格和道德的生物医学研究以及如何将科学发现传达给该领域，特别是它与癌症的生物学机制有关。Jane Johnson 博士实验室的专业知识。发育转录因子与神经内分泌肺癌、穆平博士前列腺癌实验室治疗阻力将提供成功训练所需的必要知识和技术拟议项目的经验和完成情况。