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

摘要 前列腺癌（PC）是最常见的恶性肿瘤之一，也是第二大病因 与癌症有关的男性死亡率。尽管在早期检测测试的发展方面取得了重大进展， 改善了对诊断为器官局限性PC的患者的管理， 侵袭性和转移性难治性PC（HRPC）通常导致治疗抗性、疾病 复发和患者死亡。因此，更好地了解PC的病因 需要启动和进展以及治疗抗性来鉴定新的分子治疗靶点。 最近的证据表明，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、转移和转移中提供关键功能。 远处组织、治疗抗性和疾病复发。考虑到这些进步，中央 该建议的假设是，在PC起始细胞中诱导的特定致癌产物的活化 及其后代在PC病因学和进展过程中的作用，包括EGFR和hedgehog的上调 信号传导元件，可以合作，为他们的持续增长，生存，侵袭，转移，治疗 抵抗和疾病复发。基于这一假设，长期目标是评估 受益于同时靶向EGFR和hedgehog级联，以根除PC和转移启动 细胞及其后代，并改善目前的临床抗雄激素治疗和基于紫杉醇的 针对局部侵入性、雄激素非依赖性和转移性PC的化疗。为此，我们将在 体外和体内人PC细胞模型，以及与前列腺相关的大量患者前列腺组织 致癌作用提出了三个具体目标。目的建立其特异性功能和分子机制 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启动和发展过程中的作用。AIM II将确定耐药相关的 通过激活PC中的EGF-EGFR和声刺猬级联来调节分子 干细胞/祖细胞与其后代。AIM III将确立共靶向EGFR的治疗获益 和音速刺猬途径，用于根除PC和转移起始细胞及其后代， 改善目前的临床治疗。总而言之，这些研究应描述所提供的具体功能 通过EGFR和hedgehog途径获得更恶性的PC表型和耐药 干/祖细胞及其后代用于当前的临床治疗。共靶向的治疗意义 EGFR和hedgehog级联，以消除总PC细胞群，并改善目前的抗雄激素 用于治疗PC患者并由此预防疾病复发的治疗和基于紫杉醇的化疗 病人的死亡将被确定。

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.