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

• 批准号: 10668442
• 负责人: Kathia E. Rodarte
• 金额: $ 3.63万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 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/10668442
• 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; Communication; 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; Proliferating; 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; antagonist; cancer gene expression; cancer subtypes; candidate identification; castration resistant prostate cancer; cell growth; cell type; enzalutamide; experience; gain of function; insight; knock-down; loss of function; 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; small cell lung carcinoma; survival outcome; transcription factor; tumor; tumor progression

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.

大多数患有雄激素受体（AR）驱动癌症的前列腺腺癌患者 耐药性前列腺癌（CRPC）由于对第一线雄激素剥夺疗法的抗性。最后， 作为二线治疗，患者接受了称为enzalutamide（ENZ）的潜在AR拮抗剂治疗。然而， 通过ENZ治疗的一部分CRPC患者开发神经内分泌前列腺癌（NEPC），这是一个迅速的 通过有限的疗法和生存结果差，癌症正在进展。当前了解CRPC的研究 向NEPC过渡提出了一种谱系可塑性模型，其中具有腔细胞类型的AR依赖性肿瘤 特征通过多潜电的谱系状态过渡。在治疗的选择压力下，细胞 朝着独立于AR的神经内分泌谱系的进展。几个小组发现人NEPC肿瘤 损失了RB1和TP53，在实验模型中，这两个基因的损失都需要该过渡到A 神经内分泌谱系。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 癌症，小细胞肺癌（SCLC），一种癌症，其特征是RB1和TP53的损失。在SCLC中， 转录因子ASCL1是体外肿瘤细胞生长所必需的，而在小鼠模型中形成了SCLC 这种疾病。 ASCL1存在于NEPC肿瘤和某些细胞系模型中。电流 提案旨在确定在前列腺腺癌向NEPC过渡时是否需要ASCL1，并且 在此过程中识别由ASCL1调节的基因程序。另外，导致的机制 将探索具有RB1/TP53损失的ASCL1水平升高。 ASCL1的功能丧失方法 在NEPC细胞系中，NEPC患者衍生的Xenographtics和小鼠前列腺器官模型 将进行工程的小鼠，以确定任何ASCL1在该癌症中发挥作用的作用。比较ASCL1 NEPC中与SCLC中的功能和调节可能会揭示出常见的机制和脆弱性 这些和其他神经内分泌癌。该奖学金提供了如何科学表演的培训 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，尤其是 它与癌症的生物学机制有关。简·约翰逊博士实验室的专业知识 发育转录因子和神经内分泌肺癌以及Ping Mu博士在前列腺癌中的实验室 耐药性将为成功培训提供必要的知识和技术 拟议项目的经验和完成。