Improving the Efficacy of Cisplatin-Based Cancer Chemotherapy

提高顺铂癌症化疗的疗效

• 批准号: 8146898
• 负责人: MACUS T KUO
• 金额: $ 31.8万
• 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/8146898
• 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. PUBLIC HEALTH RELEVANCE: We propose in this application to investigate the hypothesis that anti-copper drugs which have been used in the treatment of human Wilson's and Menke's diseases can be used to modulate the efficacy of cisplatin-based cancer chemotherapy. We also propose to elucidate the mechanisms by which anti- copper drugs can regulate the transport of cisplatin into cancer cells.

描述（由申请方提供）：铂（Pt）基抗肿瘤药物在治疗多种人类恶性肿瘤时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，基于顺铂（Cp）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抗性涉及多种机制，但抗性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（Cu）转运蛋白1（hCtr 1）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）细胞系与其匹配的亲本细胞系相比，hCtr 1的表达水平降低。文献中发表的基因表达谱结果也表明，与hCtr 1表达水平低的患者相比，hCtr 1表达水平升高与Cp/紫杉烷治疗的卵巢癌患者的无进展生存时间延长显著相关。这些结果表明，Cp在癌症化疗中的疗效可以通过增强hCtr 1的表达来提高。我们最近已经证明，hCtr 1的表达是转录调节细胞内铜的生物利用度和降低水平的hCtr 1在CP耐药细胞可以上调铜降低剂，导致恢复CP的敏感性。这些新的观察结果为开发使用Cu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是严格评估的关联hCtr 1表达和化疗敏感性的一个大队列的1056例卵巢癌患者铂类药物使用蛋白质组学方法。具体目的2旨在确定Cu降低剂是否可以使用表现出降低的hCtrl表达的内在CpR卵巢癌细胞系增强对基于Pt的抗肿瘤剂的化学增敏。这些降铜剂已被批准用于威尔逊病和门克病铜中毒的临床治疗，并且作为抗肿瘤血管生成剂也处于临床试验的各个阶段。具体目标3描述了降Cu剂在体内动物肿瘤模型中使Cp抗性再敏感的临床前有效性和毒性研究。具体目标4提出描绘这些铜降低剂诱导的hCtr 1上调的机制。具体目标5提出研究Cp诱导的hCtr 1上调的机制。这是一项机制驱动的研究，对使用临床批准的降铜剂改善基于铂的癌症化疗的疗效具有重要的转化意义。 公共卫生关系： 在本申请中，我们提出研究已经用于治疗人Wilson病和Menke病的抗铜药物可以用于调节基于顺铂的癌症化疗的功效的假设。我们还建议阐明抗铜药物调节顺铂转运到癌细胞中的机制。