Improving the Efficacy of Cisplatin-Based Cancer Chemotherapy

提高顺铂癌症化疗的疗效

• 批准号: 8461154
• 负责人: MACUS T KUO
• 金额: $ 29.89万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-23 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8461154
• 关键词: Affinity; Angiogenesis Inhibitors; Animal Model; Animals; Biological Availability; Cancer Center; Cancer Patient; Cancer cell line; Carboplatin; Cell Line; Cells; Chemosensitization; Chemotherapy-Oncologic Procedure; Cisplatin; Clinical Treatment; Clinical Trials; Combination Drug Therapy; Copper; DNA Microarray Chip; Data; Development; Disease; Drug Transport; Drug resistance; Drug usage; Exhibits; Future; Gene Expression; Goals; Hepatolenticular Degeneration; Homeostasis; Human; Impairment; Investigation; Laboratories; Link; Literature; Malignant Neoplasms; Malignant neoplasm of ovary; Menkes Kinky Hair Syndrome; Messenger RNA; Metabolism; Modeling; Molecular Profiling; Normal Range; Nude Mice; Operative Surgical Procedures; Patients; Penicillamine; Pharmaceutical Preparations; Pharmacotherapy; Phase; Phase II Clinical Trials; Platinum; Progression-Free Survivals; Proteins; Proteomics; Publishing; Regulation; Research; Resistance; Staging; Stress; Taxane Compound; Technology; Testicular Germ Cell Tumor; Time; Toxic effect; Treatment Failure; Triethylenetetramine; Tumor Debulking; Up-Regulation; Xenograft procedure; analog; antitumor agent; base; cancer cell; chemotherapy; clinical efficacy; cohort; cytotoxic; improved; in vivo; knowledge base; novel; orexin A receptor; oxaliplatin; pre-clinical; pre-clinical research; protein expression; public health relevance; resistance mechanism; restoration; taxane; tetrathiomolybdate; tumor; tumor xenograft

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.

描述（由申请人提供）：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。特别是在卵巢癌和睾丸生殖细胞肿瘤中，以顺铂为基础的联合化疗已成为这些疾病药物治疗的支柱。然而，对铂基药物的耐药性是治疗失败的主要原因。虽然已经认识到Cp耐药涉及多种机制，但耐药的一个重要机制是药物转运缺陷。最近的研究表明，人类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）细胞系与匹配的亲本细胞系相比，hCtr1的表达水平降低。文献中发表的基因表达谱结果也表明，在接受Cp/紫杉烷治疗的卵巢癌患者中，与低水平hCtr1表达的患者相比，hCtr1表达水平升高与更长的无进展生存时间显著相关。这些结果提示，通过提高hCtr1的表达，可以提高Cp在肿瘤化疗中的疗效。我们最近证明hCtr1的表达受细胞内Cu生物利用度的转录调节，并且在Cp抗性细胞中降低的hCtr1水平可以通过降Cu药物上调，从而恢复Cp敏感性。这些新的观察结果为开发利用降铜药物规避人类癌症中Cp耐药性的策略提供了理论依据。具体目的1是使用蛋白质组学方法批判性地评估1056名卵巢癌患者对Pt药物的hCtr1表达与化疗敏感性的关系。特异性目的2旨在确定使用hCtr1表达降低的内在CpR卵巢癌细胞系，降铜药物是否可以增强对基于Pt的抗肿瘤药物的化疗敏化。这些降铜药物已被批准用于Wilson病和Menke病的铜中毒的临床治疗，也在不同的临床试验阶段作为抗血管生成药物治疗癌症。特异性目的3描述了降铜药物在体内动物肿瘤模型中对Cp耐药再敏化的临床前疗效和毒性研究。特异性目的4提出描述这些降铜药物诱导hCtr1上调的机制。Specific Aim 5提出探讨Cp诱导hCtr1上调的机制。这是一项机制驱动的研究，对提高临床批准的降铜药物基于pt的癌症化疗的疗效具有重要的转化意义。