Disulfiram and Cisplatin in Refractory TGCTs. (DISGCT)

Description

Germ-cell tumours (GCTs) are extraordinarily chemosensitive and resemble the clinical and biological characteristics of a model for the cure of cancer. Nonetheless, a small proportion of patients do not have a durable complete remission (CR) with initial chemotherapy. Only 20-40% of them will be cured with the use of platinum-containing standard-dose or high-dose salvage chemotherapy with autologous stem cell transplantation (ASCT). Patients who fail to be cured after second-line salvage therapy have an extremely poor prognosis and long term survival had been documented in <5%. Paclitaxel plus ifosfamide and cisplatin is considered as a standard salvage chemotherapy in relapsed good prognosis GCTs, however, up to 40% of favourable prognosis patients failed to achieve durable response to this combination, and therefore new treatment strategies are warranted.

Previously, it was showed that cisplatin resistant TGCTs overexpress ALDH isoforms and inhibition of ALDH activity by disulfiram is associated with reconstitution of cisplatin sensitivity. Cisplatin-resistant TGCTs exhibited increased sensitivity to ALDH inhibitor disulfiram in vitro. Although Disulfiram (Antabuse) is an approved drug to support the treatment of chronic alcoholism, it may serve as an antitumor agent suitable for the drug repurposing in combination therapy in order to inhibit ALDH activity thus overcoming a cisplatin resistance in refractory TGCTs. Indeed, disulfiram in combination with cisplatin very efficiently eradicated platinum-resistant NTERA-2 model spheroids and significantly inhibited xenograft growth in vivo in our experimental system.

Based on aforementioned data, investigators suggest that there is strong rationale to inhibit ALDH in TGCT. Investigators hypothesize that inactivation of ALDH by disulfiram recover cisplatin sensitivity in patients with progressing or relapsing germ cell cancer.

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