Novel deregulated genes in the etiology and progression of human prostate cancer

人类前列腺癌病因和进展中的新型失调基因

• 批准号: 8494115
• 负责人: Surinder K. Batra
• 金额: $ 3.76万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8494115
• 关键词: Ablation; Adult; Aggressive behavior; Androgens; Apoptotic; Behavior; Bicalutamide; CWR22Rv1; Cancer Etiology; Cancer Patient; Caring; Castration; Cell Fraction; Cell Line; Cell model; Cells; Cessation of life; Clinical; Clinical Treatment; Development; Diagnosis; Disease Progression; Disease Resistance; Distant; Drug resistance; EGF gene; Early Diagnosis; Elements; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Epigenetic Process; Epithelial; Epithelial Cells; Erinaceidae; Etiology; GLI-1; Gefitinib; Gene Expression; Genes; Genetic; Goals; Growth; Hormones; Human; In Vitro; Investigation; Lead; MEKs; Malignant - descriptor; Malignant neoplasm of prostate; Mesenchymal; Methods; Molecular; Neoplasm Metastasis; Non-Malignant; Oncogenic; Organ; PC3 cell line; Pathway interactions; Patient Care; Patients; Pharmaceutical Preparations; Phenotype; Phospholipase; Phosphorylation; Prostate carcinoma; Prostatic; Prostatic Tissue; Proteins; Radiation therapy; Radical Prostatectomy; Recurrent disease; Refractory; Relapse; Research; Resistance; Second Primary Neoplasms; Signal Transduction; Sonic Hedgehog Pathway; Specimen; Staging; Stem cells; Techniques; Testing; Therapeutic; Tissues; Up-Regulation; Validation; androgen independent prostate cancer; base; cancer cell; cancer initiation; cell motility; chemotherapy; clinically relevant; cyclopamine; docetaxel; high risk; hormone therapy; human FRAP1 protein; human SMO protein; improved; in vivo; inhibitor/antagonist; interest; malignant phenotype; men; new therapeutic target; novel; palliative; prevent; programs; prostate carcinogenesis; self-renewal; small hairpin RNA; smoothened signaling pathway; stem; therapeutic target; tumor; tumor progression; tumorigenic

ABSTRACT Prostate cancer (PC) is among the most commonly diagnosed malignancies and the second leading cause of cancer-related deaths in men. Although significant progress in the development of early detection tests has led to improved management of patients diagnosed with organ-confined PCs, the progression to locally invasive and metastatic hormone-refractory PCs (HRPCs) typically leads to treatment resistance, disease relapse and the death of patients. Therefore, a better understanding of etiological causes responsible for PC initiation and progression and treatment resistance is needed to identify novel molecular therapeutic targets. Recent lines of evidence have revealed that the malignant transformation of adult prostatic stem/progenitor cells into highly tumorigenic PC-initiating cells may provide critical functions in PC progression, metastases at distant tissues, treatment resistance and disease relapse. In considering these advances, the central hypothesis of this proposal is that the activation of specific oncogenic products induced in PC-initiating cells and their progenies during PC etiology and progression, including an up-regulation of EGFR and hedgehog signaling elements, may cooperate for their sustained growth, survival, invasion, metastases, treatment resistance and disease relapse. Based on this hypothesis, the long-term objective is to evaluate the potential benefit to simultaneously target EGFR and hedgehog cascades for eradicating PC- and metastasis-initiating cells and their progenies and improving the current clinical anti-androgenic treatments and docetaxel-based chemotherapies against locally invasive, androgen independent and metastatic PCs. For this, we will use in vitro and in vivo human PC cell models, and a large panel of patient's prostatic tissues relevant to prostate carcinogenesis. Three specific aims are proposed. AIM I will establish the specific functions and molecular mechanisms of EGFR and hedgehog pathways in the malignant transformation of PC stem/progenitor cells and their progenies during PC initiation and progression. AIM II will identify the drug resistance-associated molecules modulated through the activation of EGF-EGFR and sonic hedgehog cascades in PC stem/progenitor cells versus their progenies. AIM III will establish the therapeutic benefit of co-targeting EGFR and sonic hedgehog pathways for eradicating PC- and metastasis-initiating cells and their progenies and improving current clinical therapies. Altogether, these studies should delineate the specific functions provided by EGFR and hedgehog pathways in the acquisition of a more malignant phenotype and resistance of PC stem/progenitor cells and their progenies to current clinical therapies. The therapeutic interest of co-targeting EGFR and hedgehog cascades to eradicate the total PC cell mass and improve current anti-androgenic treatments and docetaxel-based chemotherapies for treating PC patients and thereby prevent disease relapse and the death of patients will be established.

抽象的 前列腺癌 (PC) 是最常诊断的恶性肿瘤之一，也是第二大原因 男性癌症相关死亡。尽管早期检测测试的开发取得了重大进展 改善了对诊断为器官局限性 PC 的患者的管理，进展为局部 侵袭性和转移性激素难治性 PC (HRPC) 通常会导致治疗抵抗、疾病 复发和患者死亡。因此，更好地了解 PC 的病因 需要确定新的分子治疗靶标的起始和进展以及治疗耐药性。 最近的一系列证据表明，成人前列腺干/祖细胞的恶性转化 细胞转化为高致瘤性 PC 起始细胞可能在 PC 进展、转移中提供关键功能 远处组织、治疗抵抗和疾病复发。在考虑这些进步时，中央 该提议的假设是 PC 启动细胞中诱导的特定致癌产物的激活 及其后代在 PC 病因和进展过程中的变化，包括 EGFR 和刺猬蛋白的上调 信号元件，可能会配合它们的持续生长、生存、侵袭、转移、治疗 抵抗力和疾病复发。基于这一假设，长期目标是评估潜力 有利于同时靶向 EGFR 和刺猬级联，以根除 PC 和转移起始物 细胞及其后代，并改进当前临床抗雄激素治疗和基于多西紫杉醇的治疗 针对局部侵袭性、雄激素非依赖性和转移性 PC 的化疗。为此，我们将使用 体外和体内人类 PC 细胞模型，以及大量与前列腺相关的患者前列腺组织 致癌作用。提出了三个具体目标。 AIM 我将建立特定的功能和分子 EGFR和hedgehog通路在PC干/祖细胞恶性转化中的作用机制 及其后代在 PC 启动和进展过程中的作用。 AIM II 将识别与耐药性相关的 通过激活 PC 中的 EGF-EGFR 和音刺猬级联来调节的分子 干/祖细胞与其后代。 AIM III 将确定联合靶向 EGFR 的治疗益处 和声波刺猬途径，用于根除 PC 和转移起始细胞及其后代， 改善当前的临床治疗。总而言之，这些研究应该描述所提供的具体功能 通过EGFR和hedgehog途径获得更恶性的表型和PC耐药性 干/祖细胞及其后代目前的临床治疗。共同靶向的治疗意义 EGFR 和 Hedgehog 级联消除 PC 细胞总量并改善当前的抗雄激素治疗 用于治疗 PC 患者的治疗和基于多西紫杉醇的化疗，从而预防疾病复发 并将确定患者的死亡。