title: Overcoming platinum resistance through the use of a copper-lowering agent.
abstract: Low levels of human copper transporter 1 (hCtr1) mRNA are associated with a shorter progression-free survival after platinum-based therapy. Pretreatment with a copper-lowering agent such as trientine enhanced hCtr1-mediated platinum uptake. Therefore, we conducted a pilot study (NCT01178112) of carboplatin and trientine with the goal of resensitizing patients with advanced cancer to platinum chemotherapy. This case report reviews the outcomes of 5 patients with platinum-resistant high-grade epithelial ovarian cancer enrolled on the study to date. Overall, they tolerated treatment well. Severe adverse events that occurred in 2 patients were myelosuppression, notably anemia requiring transfusion. Dose-limiting toxicity was not observed within the first 28 days (cycle 1). After 2 cycles of therapy, partial remission was achieved in 1 patient (10+ months), stable disease in 3 patients (2, 3.5+, and 5 months, respectively), and 1 patient had progressive disease. These cases provide preliminary clinical evidence that the role of decreasing copper levels in reversing platinum resistance merits additional clinical investigation. Evaluation of this novel strategy is warranted in larger studies to assess the efficacy of this approach for treating platinum-resistant advanced epithelial ovarian cancer in patients with high copper levels.
authors.affiliation: Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. siqingfu@mdanderson.org
authors.forename: Siqing
authors.initials: S
authors.lastname: Fu
authors.forename: Aung
authors.initials: A
authors.lastname: Naing
authors.forename: Caroline
authors.initials: C
authors.lastname: Fu
authors.forename: Macus Tien
authors.initials: MT
authors.lastname: Kuo
authors.forename: Razelle
authors.initials: R
authors.lastname: Kurzrock
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D016190:Carboplatin / Q000627:therapeutic use*; D000077216:Carcinoma, Ovarian Epithelial; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism; D002614:Chelating Agents / Q000627:therapeutic use*; D003300:Copper / Q000378:metabolism*; D000079923:Copper Transporter 1; D019008:Drug Resistance, Neoplasm; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008875:Middle Aged; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010865:Pilot Projects; D014266:Trientine / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D027682:Cation Transport Proteins; D002614:Chelating Agents; D000079923:Copper Transporter 1; C490079:SLC31A1 protein, human; D003300:Copper; D016190:Carboplatin; D014266:Trientine