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.
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.
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