Molecular mechanisms underlying lineage plasticity in prostate cancer

前列腺癌谱系可塑性的分子机制

• 批准号: 10596605
• 负责人: Himisha Beltran
• 金额: $ 58.27万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 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/10596605
• 关键词: ASCL1 gene; Acceleration; Adenocarcinoma; Androgen Receptor; Androgens; Area; Automobile Driving; Biological Models; Bypass; Cancer Patient; 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; Prognosis; 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; Tumor Escape; Tumor Promotion; Up-Regulation; Work; cancer care; cancer cell; cancer initiation; cancer therapy; cancer type; castration resistant prostate cancer; chromatin remodeling; combinatorial; data modeling; effective therapy; improved; inhibitor; insulinoma associated 1; 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; small cell lung carcinoma; stem; targeted treatment; therapeutically effective; therapy resistant; transcription factor; transcriptional reprogramming; tumor; tumor growth; tumor progression

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.

项目摘要/摘要 前列腺癌是作为一种雄激素驱动疾病以及针对的全身疗法 雄激素受体（AR）用于在疾病的所有阶段治疗患者。近年来， 较早，更有效的AR靶向新药物，独立于AR的前列腺癌 出现了。我们发现这与谱系可塑性有关 治疗压力，肿瘤通过失去腔内前列腺身份（包括 AR）以及收购包括神经/神经内分泌的替代谱系程序，类似茎状的 和发展途径。在极端情况下，肿瘤可能会完全从AR- 阳性前列腺腺癌（PADC）朝着Ar-阴性的小细胞/神经内分泌 癌（NEPC）。这种表型变化与临床和分子特征相似 小细胞肺癌，表现为快速进展和致命疾病。我们已经整合了 患者和临床前数据以识别和分子表征驱动的基因和途径 谱系可塑性，包括TP53/RB1的综合损失，抑制Notch信号 途径和谱系确定转录因子（LDTF）的上调，包括ASCL1和 INSM1。我们假设Notch信号丢失激活LDTF，该LDTF与 超级增强剂和染色质调节剂可驱动谱系可塑性，AR信号的丧失 依赖性和NEPC的进展。为了检验这一假设，我们将研究Notch-的作用 INSM1信号传导调节LDTF以驱动NEPC进展和耐药性（AIM 1）； 广泛地表征超增强剂的景观和转录重编程 控制谱系可塑性（AIM 2）；并阐明促进LDTF的转录网络 从AR驱动状态到非AR驱动疾病的肿瘤进化（AIM 3）。该提议将 不仅增强了我们对肿瘤进化和细胞身份的理解，还将确定新的 靶向谱系可塑性的治疗方法。这些是改善的关键步骤 前列腺癌患者的早期检测，治疗和死亡率产生了治疗抗药性。 结果也可能与其他癌症类型相关，以发展谱系可塑性以逃避 有效的靶向疗法，例如肺癌，黑色素瘤和乳腺癌。