Defining and Characterizing Drivers of Lethal Metastatic Prostate Cancer

致命性转移性前列腺癌的驱动因素的定义和特征

• 批准号: 10714242
• 负责人: Grinu Mathew
• 金额: $ 28.09万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-03-16 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10714242
• 关键词: American; Behavior; Biochemical; Biological Assay; Biology; Cancer Etiology; Cancer Patient; Cell Line; Cells; Cellular biology; Cessation of life; Chromosome Mapping; Clustered Regularly Interspaced Short Palindromic Repeats; Collaborations; Collection; Compensation; Copy Number Polymorphism; DNA Sequence Alteration; Data; Data Set; Dependence; Development; Disease; Early Diagnosis; Event; Genes; Genetic; Genetically Engineered Mouse; Genomic approach; Genotype; Goals; Growth; Human; Image; Indolent; Isogenic transplantation; Link; Maintenance; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Metastatic Prostate Cancer; Modeling; Molecular; Molecular Target; Mus; Nebraska; Neoplasm Metastasis; Oncogenes; Organ; Organoids; PIK3CG gene; PTEN gene; Patient Care; Patients; Phenotype; Phosphotransferases; Primary Lesion; Prostate; Protac; Receptor Protein-Tyrosine Kinases; Receptor Signaling; Reproducibility; Research; Resistance; Role; Sampling; Shapes; Signal Induction; Signal Transduction; Stress; TP53 gene; Techniques; Testing; Therapeutic; Tumor Cell Line; Tyrosine; Work; advanced disease; androgen deprivation therapy; axl receptor tyrosine kinase; cancer cell; castration resistant prostate cancer; cell type; clinical translation; cohort; curative treatments; genetic approach; in vivo; men; mouse genetics; mouse model; novel; pharmacologic; phosphoproteomics; prostate cancer cell; prostate cancer metastasis; receptor; standard of care; trait; transcriptomic profiling; transcriptomics; translational oncology; transplant model

Project Summary: "Defining and Characterizing Drivers of Lethal Metastatic Prostate Cancer" Prostate cancer (PC) is the second leading cause of cancer-related deaths in the USA. PC is a slow growing disease, curable if detected early. However, the treatment resistant lethal form of PC is fast growing and metastatic. The goal of our proposed research is to identify genetic factors that are essential for the switch from indolent to lethal metastatic PC. We have generated a unique collection of a) PC patient derived organoids and b) primary cell lines from the tumor and metastasis of the RapidCaP mouse model for lethal PC (PTEN and TP53 deficient). Our preliminary data highlights a fundamental shift in cellular phenotype and growth signaling associated with the transition to metastasis. Most importantly, the loss of TAM kinase receptor Axl is key to this metastasis associated cellular reprogramming event. These discrete cellular states are associated with divergent signaling behavior, which enables or restricts the metastatic potential of cancer cells. Therefore, we now focus on the receptor tyrosine kinase Axl and its control of the switch from primary to metastatic disease in vivo. In this proposal we will mechanistically validate the role of Axl receptor in PC cellular lineage reprogramming and maintenance of pro-metastatic phenotype (Aim 1). Next, we will assess the effect of androgen deprivation therapy (ADT) on a relevant mouse model of Axl-deficient PC and perform transcriptomic profiling to identify molecular changes occurring under the stress of ADT (Aim 2). To develop therapeutic strategies we will use a phosphoproteome approach and identify targetable kinase dependencies in these Axl-deficient metastatic cells (Aim 3). To execute the proposed aims, we will closely collaborate with experts in receptor signaling and PC disease biology. Our background in mouse genetics, cell biology and translational oncology is well aligned with the expertise required to carry out the proposed work and unravel the genetic dependencies of lethal metastatic PC cells.

项目总结：“致命性转移性前列腺癌的定义和特征” 前列腺癌(PC)是美国癌症相关死亡的第二大原因。PC是一种增长缓慢的产品 疾病，如果及早发现是可以治愈的。然而，耐药致死型PC正在快速增长和 转移性的。我们提出的研究的目标是确定对这种转变至关重要的遗传因素。 从懒惰到致命的转移性PC。我们已经生成了)PC患者派生的独特集合 致死性PC的RapidCaP小鼠模型肿瘤和转移的原代细胞系 (PTEN和TP53缺失)。我们的初步数据突显了细胞表型和 与转移转移相关的生长信号。最重要的是，激酶受体的丧失 AXL是这种与转移相关的细胞重编程事件的关键。这些离散的细胞状态是 与不同的信号行为有关，这种行为允许或限制癌细胞的转移潜力。 因此，我们现在集中在受体酪氨酸激酶Axl及其对从初级到 体内转移性疾病。在这项建议中，我们将从机械上验证Axl受体在PC中的作用 细胞谱系重编程和前转移表型的维持(目标1)。接下来，我们将评估 雄激素剥夺疗法(ADT)对AXL缺陷型PC和Performance相关小鼠模型的影响 转录图谱以确定在ADT压力下发生的分子变化(目标2)。发展，发展 治疗策略：我们将使用磷酸蛋白质组方法并确定靶向的激酶依赖性。 在这些Axl缺陷的转移细胞中(目标3)。为落实建议的目标，我们会与 受体信号和PC疾病生物学方面的专家。我们在小鼠遗传学、细胞生物学和 翻译肿瘤学很好地与执行拟议的工作和揭示所需的专业知识保持一致 致死性转移PC细胞的遗传依赖性。