Determining the role of ASCL1 in neuroendocrine prostate cancer

前列腺癌是一种雄激素受体(AR)驱动的癌症，大多数患者发生去势 耐药前列腺癌(CRPC)由于对一线雄激素剥夺疗法产生抵抗。因此， 作为二线治疗，患者接受一种名为苯扎鲁胺(ENZ)的有效AR拮抗剂的治疗。然而， 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 进展中的癌症，治疗有限，生存结果不佳。理解CRPC的最新研究 向NEPC的转变表明了一种谱系可塑性模型，其中AR依赖的肿瘤具有管腔细胞型 功能通过多潜能世系状态的转变。在治疗的选择压力下，细胞 AR非依赖性神经内分泌谱系的研究进展。几个小组已经发现了人类NEPC肿瘤 已经丢失了RB1和TP53，在实验模型中，这两个基因的丢失是向 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)，也是一种以RB1和TP53缺失为特征的癌症。在SCLC中， 转录因子ASCL1是肿瘤细胞体外生长和小鼠模型小细胞肺癌形成所必需的 这种疾病。ASCL1存在于NEPC肿瘤和某些疾病的细胞系模型中。海流 该提案旨在确定在前列腺癌向NEPC的转变过程中是否需要ASCL1，以及 确定在这一过程中受ASCL1调控的基因程序。此外，导致 本研究将探讨伴有RB1/TP53缺失的ASCL1水平升高。ASCL1的增益法和损失法 在NEPC细胞系、NEPC患者来源的异种移植和小鼠前列腺器官模型中 将对转基因小鼠进行实验，以确定ASCL1是否在这种癌症中扮演了什么角色。比较ASCL1 NEPC的功能和监管与SCLC的功能和监管可能揭示共同的机制和漏洞 这些癌症和其他神经内分泌癌。该奖学金提供如何科学地执行任务的培训。 严谨和合乎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。简·约翰逊博士实验室的专业知识 发育转录因子与神经内分泌肺癌，以及平木博士的实验室在前列腺癌中的作用 治疗阻力将提供成功培训所需的必要知识和技术 拟议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.