Improving the Efficacy of Cisplatin-Based Cancer Chemotherapy

描述(申请人提供)：铂(铂)基抗肿瘤药物在许多人类恶性肿瘤的治疗中具有显著的抗肿瘤活性。尤其是在卵巢癌和睾丸生殖细胞肿瘤中，以顺铂(CP)为基础的联合化疗已成为这些疾病药物治疗的支柱。然而，对铂类药物的耐药性是治疗失败的主要原因。虽然目前已认识到CP耐药涉及多种机制，但药物转运缺陷是其中一个重要的耐药机制。最近的研究表明，人高亲和力铜转运蛋白1(HCtr1)是顺铂及其类似物卡铂和奥沙利铂的功能性转运蛋白。我们实验室的初步结果表明，许多已建立的顺铂耐药(CPR)细胞株与其匹配的亲本细胞株相比，hCtr1的表达水平降低。发表在文献中的基因表达谱结果还表明，与hCtr1表达水平低的患者相比，接受CP/紫杉烷治疗的卵巢癌患者的hCtr1表达水平升高与更长的无进展生存时间显著相关。这些结果表明，CP可以通过增强hCtr1的表达来提高其在肿瘤化疗中的疗效。我们最近已经证明，hCtr1的表达受细胞内铜生物有效性的转录调控，并且铜离子降低剂可以上调CP抗性细胞中hCtr1的水平，导致CP敏感性的恢复。这些新颖的观察结果为开发利用铜降低剂规避人类癌症中CP耐药性的策略提供了理论基础。提出了五个具体目标：具体目标1利用蛋白质组学方法评价1056例卵巢癌患者中hCtr1的表达与铂类药物化疗敏感性的关系。特定目的2试图利用表现出hCtr1表达降低的内在CPR卵巢癌细胞株，确定铜降低剂是否可以增强对铂类抗肿瘤药物的化疗敏感性。这些降铜药已被批准用于临床治疗肝豆状核变性和门克病的铜中毒，并正处于抗肿瘤血管生成药物的不同临床试验阶段。具体目的3描述了铜降低剂在动物体内肿瘤模型中对环磷酰胺耐药再增敏的临床前疗效和毒性研究。具体目标4提出了这些铜降低剂诱导hCtr1上调的机制。目的5研究CP诱导hCtr1表达上调的机制。这是一项机制驱动的研究，对使用临床批准的铜降压剂提高基于铂的癌症化疗的疗效具有重要的翻译意义。

DESCRIPTION (provided by applicant): Platinum (Pt)-based antitumor agents have significant antitumor activity in the treatments of many human malignancies. Especially in ovarian cancers and in testicular germ cell tumors, cisplatin (Cp)-based combination chemotherapy has been a pillar of drug therapy of these diseases. However, resistance to Pt- based agents is the major cause of treatment failure. While it has been recognized that multiple mechanisms are involved in Cp resistance, one important mechanism of resistance is defective drug transport. Recent studies have indicated that the human high-affinity copper (Cu) transporter 1 (hCtr1) is a functional transporter of cisplatin and its analogues, carboplatin and oxaliplatin. Preliminary results from our laboratory have demonstrated that many established cisplatin-resistant (CpR) cell lines exhibit reduced expression levels of hCtr1 compared with those in their matched parental cell lines. Results from gene expression profiles published in the literature also suggested that elevated expression levels of hCtr1 are significantly correlated with longer progression-free survival time in ovarian cancer patients treated with Cp/taxane than in patients with low levels of hCtr1 expression. These results suggest that the efficacy of Cp in cancer chemotherapy can be improved through enhancing hCtr1 expression. We have recently demonstrated that expression of hCtr1 is transcriptionally regulated by intracellular Cu bioavailability and that reduced levels of hCtr1 in Cp-resistant cells can be up-regulated by Cu-lowering agents, leading to a restoration of Cp sensitivity. These novel observations provide the rationale for the development of strategies for circumventing Cp resistance in human cancers using Cu-lowering agents. Five specific aims are proposed: Specific Aim 1 is to critically evaluate the association of hCtr1 expression and chemosensitivity of a large cohort of 1056 ovarian cancer patients to Pt drugs using proteomic approach. Specific Aim 2 seeks to determine whether Cu-lowering agents can enhance chemosensitization to Pt- based antitumor agents using intrinsic CpR ovarian cancer cell lines exhibiting reduced hCtr1 expression. These Cu-lowering agents have been approved for the clinical treatment of Cu toxicosis in Wilson disease and in Menke disease and also are in various stages of clinical trials as anti-angiogenic agents against cancers. Specific Aim 3 describes a pre-clinical efficacy and toxicity study of Cu-lowering agents to resensitize Cp resistance in in vivo animal tumor models. Specific Aim 4 proposes to delineate the mechanisms of hCtr1 upregulation induced by these Cu-lowering agents. Specific Aim 5 proposes to investigate the mechanisms of hCtr1 upregulation induced by Cp. This is mechanism-driven research that has important translational implications to improve the efficacy of Pt-based cancer chemotherapy using clinically approved Cu-lowering agents.