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.

©2012 AACR

Figures

Figure 1

Trientine structure.

Figure 2

Changes in tumor sizes, CA-125, serum ceruloplasmin, and copper levels in 5 patients with platinum-resistant high-grade epithelial ovarian cancer who received 2 cycles of therapy with trientine and carboplatin. All patients received carboplatin at AUC 6, except for patient 1 who received carboplatin at AUC 4. Patient 5 had a BRCA1 mutation.

Figure 3

Tumor responses in patient 2 in 2 panels of computed tomography (CT) scans of chest, abdomen, and pelvis. Tumor resolution of mediastinal lymphadenopathy and reduction of abdominal wall mass, peritoneal implants, and right inguinal lymphadenopathy are indicated by white arrows. The left panels represent CT scans prior to study enrollment, and the right panels are of corresponding sites after 6 cycles of therapy with carboplatin plus trientine, respectively.

Figure 4

Changes in the levels of tumor marker CA-125, serum ceruloplasmin, and copper after treatment with carboplatin plus trientine in patient 2 in A, B, and C, respectively. Decreases in the CA-125 tumor marker (A) were associated with decreases in serum ceruloplasmin levels (B), and serum copper levels (C).