Abstract 2999: Low-dose demethylation therapy for the treatment of cisplatin-resistant testicular cancer

Abstract

Abstract Testicular germ cell tumors (TGCTs) are the most common cancers of young males. A portion of TGCT patients are refractory to cisplatin. Only 30% of patients refractory to cisplatin respond to salvage therapies while to remainder die from progressive disease. Embryonal carcinoma (EC) are the stem cells of TGCTs. We have found that EC cells were highly sensitive to the DNA methyltransferase inhibitor, 5-aza deoxycytidine (5-aza). As an initial step in bringing demethylation therapy to the clinic for TGCT patients, we evaluated the effects of the clinically optimized, second generation demethylating agent guadecitabine (SGI-110) on EC cells in an animal model of cisplatin refractory testicular cancer. EC cells were exquisitely sensitive to guadecitabine and the hypersensitivity was dependent on high levels of DNA methyltransferase 3B. Guadecitabine mediated transcriptional reprogramming of EC cells included induction of p53 targets and repression of pluripotency genes. As a single agent, guadecitabine completely abolished progression and induced complete regression of cisplatin resistant EC xenografts even at doses well below those required to impact somatic solid tumors. Low dose guadecitabine also sensitized refractory EC cells to cisplatin in vivo. Genome-wide analysis indicated that in vivo antitumor activity was associated with activation of p53 and immune-related pathways and the antitumor effects of guadecitabine were dependent on p53, a gene rarely mutated in TGCTs. Together, these preclinical findings provided the rationale for our recently initiated and promising phase I clinical trial using SGI-110 to treat cisplatin refractory TGCT patients. We discuss our recent genome-wide molecular studies aimed to identify potential mechanism(s) to account for the hypersensitivity of TGCTs to 5-aza including promoter demethylation, p53 activation and dsRNA MDA5/MAVS/IRF7 viral mimicry. We also discuss preliminary findings from our ongoing trial. Our findings suggest that guadecitabine alone or in combination with cisplatin is a promising strategy to treat refractory TGCT patients. Citation Format: Andrea Corbet, Costantine Albany, Emmanuel Bikorimana, Ema Khan, Jennifer Rodriguez, Brock C. Christensen, George Sandusky, Lawrence H. Einhorn, Sarah J. Freemantle, Michael J. Spinella. Low-dose demethylation therapy for the treatment of cisplatin-resistant testicular cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2999.