Molecular mechanisms underlying lineage plasticity in prostate cancer

前列腺癌谱系可塑性的分子机制

基本信息

批准号：
10375455
负责人：
Himisha Beltran
金额：
$ 59.46万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-15 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10375455
关键词：
ASCL1 gene Adenocarcinoma Androgen Receptor Androgens Area Automobile Driving Biological Models Bypass Cancer Patient Cancer Prognosis Cell Survival Cells Chromatin Chromatin Structure Clinical DNA Methylation DNA Sequence Alteration Data Dependence Development Disease Disease Progression Drug Targeting Drug resistance Early Diagnosis Enhancers Epigenetic Process Event Evolution Gene Expression Genes Genetic Transcription Goals Growth Incidence Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of prostate Molecular Neuroendocrine Carcinoma Neuroendocrine Cell Neuroendocrine Prostate Cancer Neurons Neurosecretory Systems Normal Cell Notch Signaling Pathway Oncogenic Pathogenesis Pathway interactions Patients Phenotype Pre-Clinical Model Process Prostate Prostate Adenocarcinoma Publishing RB1 gene Receptor Inhibition Receptor Signaling Regulatory Element Resistance Role Shapes Signal Pathway Signal Transduction Solid Neoplasm Systemic Therapy TP53 gene Testing Therapeutic Up-Regulation Work base cancer care cancer cell cancer initiation cancer therapy cancer type castration resistant prostate cancer chromatin remodeling combinatorial data modeling effective therapy improved inhibitor lung small cell carcinoma malignant breast neoplasm melanoma men methylation pattern mortality neoplastic cell neuroendocrine differentiation notch protein novel therapeutic intervention novel therapeutics pre-clinical pressure programs prostate cancer cell prostate cancer progression resistance mechanism restoration stem targeted treatment therapeutically effective therapy resistant transcription factor transcriptional reprogramming tumor tumor growth tumor progression

项目摘要

Project Summary/Abstract Prostate cancer arises as an androgen driven disease, and systemic therapies that target the androgen receptor (AR) are used to treat patients at all stages of the disease. In recent years, with the earlier and more potent targeting of the AR with newer drugs, AR-independent prostate cancer has emerged. We have found that this is associated with lineage plasticity in which upon selective therapeutic pressure, tumors evade AR-therapy through loss of luminal prostate identity (including AR) and the acquisition of alternative lineage programs including neuronal/neuroendocrine, stem-like, and developmental pathways. In extreme cases, tumors may completely transition from an AR- positive prostate adenocarcinoma (PADC) toward an AR-negative small cell/neuroendocrine carcinoma (NEPC). This phenotypic change is associated with clinical and molecular features similar to small cell lung cancer, manifest by rapid progression and lethal disease. We have integrated patient and preclinical data to identify and molecularly characterize genes and pathways that drive lineage plasticity including the combined loss of TP53/RB1, suppression of the Notch signaling pathway, and up-regulation of lineage-determining transcription factors (LDTFs) including ASCL1 and INSM1. We hypothesize that loss of Notch signaling activates LDTFs, which act coordinately with super-enhancers and chromatin regulators to drive lineage plasticity, loss of AR signaling dependence, and NEPC progression. To test this hypothesis, we will investigate the role of NOTCH- INSM1 signaling in regulating LDTFs to drive NEPC progression and treatment resistance (Aim 1); extensively characterize the super-enhancer landscape and transcriptional reprogramming that governs lineage plasticity (Aim 2); and elucidate the transcriptional network of LDTFs that promote tumor evolution from an AR-driven state towards non-AR driven disease (Aim 3). This proposal will not only enhance our understanding of tumor evolution and cell identity, but will also identify new therapeutic approaches to target lineage plasticity. These are critical steps towards improving the early detection, treatment, and mortality of prostate cancer patients developing treatment resistance. Results may also have relevance in other cancer types that develop lineage plasticity to evade effective targeted therapies, such as lung cancer, melanoma, and breast cancer.

项目概要/摘要前列腺癌是一种雄激素驱动的疾病，而针对前列腺癌的全身治疗雄激素受体（AR）用于治疗疾病各个阶段的患者。近年来，随着更新药物更早、更有效地针对 AR 进行靶向治疗，即不依赖 AR 的前列腺癌已经出现了。我们发现这与谱系可塑性有关，其中选择性在治疗压力下，肿瘤通过失去前列腺管腔特性（包括 AR）和替代谱系程序的获得，包括神经元/神经内分泌、干细胞样、和发展途径。在极端情况下，肿瘤可能完全从 AR-转变阳性前列腺腺癌 (PADC) 向 AR 阴性小细胞/神经内分泌癌（NEPC）。这种表型变化与类似的临床和分子特征相关小细胞肺癌，表现为快速进展和致命疾病。我们已经集成了患者和临床前数据，以识别和分子表征驱动基因和途径谱系可塑性，包括 TP53/RB1 的联合丢失、Notch 信号传导的抑制途径，以及谱系决定转录因子 (LDTF) 的上调，包括 ASCL1 和 INSM1。我们假设 Notch 信号传导的丧失会激活 LDTF，而 LDTF 与超级增强子和染色质调节子驱动谱系可塑性、AR信号丢失依赖性和 NEPC 进展。为了检验这个假设，我们将研究 NOTCH-的作用 INSM1 信号传导调节 LDTF 以驱动 NEPC 进展和治疗耐药（目标 1）；广泛描述了超级增强子景观和转录重编程控制谱系可塑性（目标 2）；并阐明 LDTF 的转录网络，促进肿瘤从 AR 驱动状态演变为非 AR 驱动疾病（目标 3）。该提案将不仅增强我们对肿瘤进化和细胞身份的理解，而且还将发现新的以谱系可塑性为目标的治疗方法。这些是改善环境的关键步骤前列腺癌患者出现治疗耐药性的早期发现、治疗和死亡率。结果也可能与其他癌症类型相关，这些癌症类型发展出谱系可塑性以逃避有效的靶向治疗，例如肺癌、黑色素瘤和乳腺癌。