Results of a Phase II Trial of Gemcitabine Plus Doxorubicin in Patients with Recurrent Head and Neck Cancers: Serum C18-Ceramide as a Novel Biomarker for Monitoring Response

Abstract

Purpose Here we report a phase II clinical trial, which was designed to test a novel hypothesis that treatment with GEM/DOX would be efficacious via reconstitution of C18-ceramide signaling in HNSCC patients for whom first-line platinum-based therapy failed. Experimental Design Patients received GEM (1,000 mg/m2) and DOX (25 mg/m2) on days 1 and 8, every 21 days, until disease progression. After completion of 2 treatment cycles, patients were assessed radiographically, and serum samples were taken for sphingolipid measurements. Results We enrolled 18 patients in the trial, who were evaluable for toxicity, and 17 for response. The most common toxicity was neutropenia, observed in 9 of 18 patients, and there were no major non-hematological toxicities. Of the 17 patients, 5 patients had progressive disease (PD), 1 had complete response (CR), 3 exhibited partial response (PR), and 8 had stable disease (SD). The median progression-free survival (PFS) was 1.6 months (95% CI, 1.4, 4.2) with a median survival of 5.6 months (95% CI, 3.8, 18.2). Remarkably, serum sphingolipid analysis revealed significant differences in patterns of C18-ceramide elevation in patients with CR/PR/SD in comparison to patients with PD, indicating the reconstitution of tumor suppressor ceramide generation by GEM/DOX treatment. Conclusions Our data suggest that the GEM/DOX combination could represent an effective treatment for some patients with recurrent or metastatic HNSCC, and that serum C18-ceramide elevation might be a novel serum biomarker of chemotherapy response.

Radiation-induced acid ceramidase confers prostate cancer resistance and tumor relapse

“…These results suggest associations between a 2-fold increase of the overall intracellular ceramide burden, and/or specifically among the C 16 -ceramide species, and AC induction. Investigations to distinguish differences in sphingolipid profile expression between "normal" versus malignant cells at baseline or in vitro growth conditions have identified higher levels of ceramide expression in cancer tissues and cells as well as species-specific variations (63,64). At the level of enzymatic function, elucidating the control of sphingolipids upon chemotherapeutic or radiotherapeutic challenge may yield novel differences between cell types (65)(66)(67)(68)(69)(70).…”

Ceramide induced mitophagy and tumor suppression

“…CerS1/C 18 -ceramide axis leads to cancer cell death and decreases head and neck tumor growth [34-36]. Increased levels of serum C 18 -ceramide act as a potential biomarker to monitor patients’ response to chemotherapy [37]. On the other hand, C 16 -ceramide promotes head and neck cancer cell proliferation and its increased serum levels associate with a positive lymph node status in breast cancer patients [38, 39].…”

Autophagy paradox and ceramide

“…Cer has been shown to act as a novel biomarker of cancer therapy response[147], as well as a potential target for the generation of chemotherapeutics[148,149]. In this review, we mainly described the role of Cer in lethal autophagy regulation, which might be an essential mechanism Cer utilize to induce cell killing.…”