Determining the role of ASCL1 in neuroendocrine prostate cancer

大多数前列腺癌患者，雄激素受体（AR）驱动的癌症，发展去势 耐药前列腺癌（CRPC）由于一线雄激素剥夺疗法的耐药性。因此，委员会认为， 作为二线疗法，患者用称为恩杂鲁胺（Enz）的有效AR拮抗剂治疗。然而，在这方面， 一部分接受Enz治疗的CRPC患者发生神经内分泌前列腺癌（NEPC），这是一种快速的 进展性癌症，治疗有限，生存结果差。了解CRPC的当前研究 向NEPC的转变提示了谱系可塑性模型，其中具有管腔细胞类型的AR依赖性肿瘤 特征通过多电位谱系状态转变。在治疗的选择压力下，细胞 向AR非依赖性神经内分泌谱系发展。几个研究小组已经发现了人类NEPC肿瘤 已经失去了RB 1和TP 53，在实验模型中，这两个基因的损失是需要这种过渡到 神经内分泌谱系值得注意的是，NEPC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），一种也以RB 1和TP 53缺失为特征的癌症。在SCLC中， 转录因子ASCL 1是体外肿瘤细胞生长和小鼠模型中SCLC形成所必需的 这种疾病。ASCL 1存在于NEPC肿瘤和该疾病的一些细胞系模型中。当前 该提案旨在确定前列腺腺癌向NEPC的转变是否需要ASCL 1， 鉴定在此过程中由ASCL 1调控的基因程序。此外，导致 将探索升高的ASCL 1水平和RB 1/TP 53损失。ASCL 1的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小鼠前列腺类器官模型中， 工程小鼠将进行，以确定如果任何ASCL 1在这种癌症中发挥什么作用。比较ASCL 1 NEPC与SCLC的功能和调节可能揭示了NEPC的共同机制和脆弱性， 这些和其他神经内分泌癌。该奖学金提供如何科学地执行 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 它涉及癌症的生物学机制。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，以及平穆博士的前列腺癌实验室 治疗阻力将提供成功训练所需的必要知识和技术 项目的经验和完成情况。

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.