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

描述(申请人提供)：前列腺癌(PC)是最常见的恶性肿瘤之一，也是男性癌症相关死亡的第二大原因。尽管早期检测测试的发展取得了重大进展，改善了对被诊断为器官受限PC的患者的管理，但向局部侵袭性和转移性激素耐药PC(HRPC)的进展通常会导致治疗耐药、疾病复发和患者死亡。因此，需要更好地了解PC发生、发展和治疗耐药的病因，以确定新的分子治疗靶点。最近的一系列证据表明，成年前列腺干细胞/祖细胞恶性转化为高致瘤性的PC启动细胞可能在PC进展、远处组织转移、治疗耐药和疾病复发中起关键作用。考虑到这些进展，这一建议的中心假设是，在PC的病因和进展过程中，PC启动细胞及其后代中诱导的特定致癌产物的激活，包括EGFR和Hedgehog信号元件的上调，可能与它们的持续生长、生存、侵袭、转移、治疗耐药和疾病复发协同作用。基于这一假设，长期目标是评估同时靶向EGFR和Hedgehog级联疗法在根除PC和转移启动细胞及其后代方面的潜在益处，并改进目前临床上针对局部侵袭性、雄激素非依赖性和转移性PC的抗雄激素治疗和基于多西紫杉醇的化疗。为此，我们将使用体外和体内的人类PC细胞模型，以及与前列腺癌发生相关的一大组患者的前列腺组织。提出了三个具体目标。目的探讨EGFR和Hedgehog信号转导通路在PC发生发展过程中对PC干/祖细胞及其后代恶性转化的作用和分子机制。目的II将确定通过激活EGF-EGFR和PC干/祖细胞中的Sonic Hedgehog级联而与其后代相比调节的耐药相关分子。目的III将确定共同靶向EGFR和Sonic Hedgehog通路的治疗益处，以根除PC和转移起始细胞及其后代，并改进当前的临床治疗。总之，这些研究应该勾勒出EGFR和Hedgehog通路在获得更恶性的表型和PC干细胞/祖细胞及其后代对当前临床治疗的抵抗力方面所起的特殊作用。联合靶向EGFR和Hedgehog的治疗兴趣将被确立，以根除总的PC细胞团，并改进目前用于治疗PC患者的抗雄激素治疗和基于多西紫杉醇的化疗，从而防止疾病复发和患者死亡。 公共卫生相关性： 该研究计划旨在确定EGFR和Hedgehog级联以及其他相互作用的通路在PC干细胞/祖细胞及其后代的恶性转化和治疗耐药性中的意义，并验证新的治疗靶点，以改进当前的治疗方法，防止疾病复发和PC患者的死亡。这些研究将包括描绘通过EGFR和Hedgehog通路调节的基因产物，这些基因产物可以在前列腺癌的进展和治疗耐药性中协同作用，并通过使用人类PC细胞模型和与前列腺癌发生相关的患者的前列腺组织样本来验证根除总PC细胞团的新的治疗靶点。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: The research program aims to establish the implications of EGFR and hedgehog cascades and other interacting pathways in the malignant transformation of PC stem/progenitor cells and their progenies and treatment resistance and validate novel therapeutic targets for improving current therapies and preventing disease relapse and the death of PC patients. The studies will consist to delineate the gene products modulated through the EGFR and hedgehog pathways that can cooperate in PC progression and treatment resistance and validate novel therapeutic targets for eradicating total PC cell mass by using human PC cell models and prostatic tissue specimens from patients relevant to prostate carcinogenesis.