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

描述（由申请人提供）：前列腺癌（PC）是最常诊断的恶性肿瘤之一，也是男性癌症相关死亡的第二大原因。尽管早期检测检测的发展取得了重大进展，改善了对诊断为器官局限性PC的患者的管理，但进展为局部侵袭性和转移性难治性PC（HRPC）通常会导致治疗耐药性、疾病复发和患者死亡。因此，需要更好地了解导致PC发生和进展以及治疗耐药的病因，以确定新的分子治疗靶点。最近的证据表明，成人前列腺干/祖细胞恶性转化为高致瘤性PC起始细胞可能在PC进展、远处组织转移、治疗抗性和疾病复发中提供关键功能。在考虑这些进展时，该提议的中心假设是在PC病因学和进展期间在PC起始细胞及其后代中诱导的特定致癌产物的活化，包括EGFR和hedgehog信号传导元件的上调，可能对它们的持续生长、存活、侵袭、转移、治疗抗性和疾病复发起作用。基于这一假设，长期目标是评价同时靶向EGFR和hedgehog级联的潜在获益，以根除PC和转移起始细胞及其后代，并改善目前针对局部侵袭性、雄激素非依赖性和转移性PC的临床抗雄激素治疗和基于紫杉醇的化疗。为此，我们将使用体外和体内人PC细胞模型，以及与前列腺癌发生相关的大量患者前列腺组织。提出了三个具体目标。目的探讨表皮生长因子受体（EGFR）和hedgehog信号通路在前列腺癌（PC）发生、发展过程中，在PC干/祖细胞及其子代细胞恶性转化中的特异性功能和分子机制。AIM II将通过激活PC干/祖细胞与其后代中的EGF-EGFR和音刺猬级联来识别耐药相关分子。AIM III将建立共同靶向EGFR和音刺猬通路的治疗益处，用于根除PC和转移起始细胞及其后代，并改善当前的临床治疗。总之，这些研究应该描绘EGFR和刺猬途径在获得更恶性表型和PC干/祖细胞及其后代对当前临床治疗的抗性中提供的特定功能。将确立共同靶向EGFR和hedgehog级联以根除总PC细胞团并改善目前用于治疗PC患者的抗雄激素治疗和基于紫杉醇的化疗从而预防疾病复发和患者死亡的治疗利益。 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途径在PC干/祖细胞及其后代恶性转化和治疗抗性中的意义，并验证新的治疗靶点，以改善当前的治疗方法，预防疾病复发和PC患者死亡。这些研究将包括描述通过EGFR和hedgehog途径调节的基因产物，这些基因产物可以在PC进展和治疗耐药性中发挥作用，并通过使用人PC细胞模型和前列腺癌相关患者的前列腺组织标本来验证根除总PC细胞群的新治疗靶点。

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.