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Published on: March 28, 2021
Refractory testicular germ cell tumors are highly sensitive to the second generation DNA methylation inhibitor
Costantine Albany1, Mary P Hever-Jardine2, Katherine M von Herrmann2
1Division of Hematology/Oncology, Melvin and Bren Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN, USA.
Abstract:
Testicular germ cell tumors (TGCTs) are the most common cancers of young males. A substantial portion of TGCT patients are refractory to cisplatin. There are no effective therapies for these patients, many of whom die from progressive disease. Embryonal carcinoma (EC) are the stem cells of TGCTs. In prior in vitro studies we found that EC cells were highly sensitive to the DNA methyltransferase inhibitor, 5-aza deoxycytidine (5-aza). Here, 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. These preclinical findings suggest that guadecitabine alone or in combination with cisplatin is a promising strategy to treat refractory TGCT patients.
Insights
Guadecitabine effectively treats cisplatin-refractory testicular germ cell tumors (TGCTs) by reprogramming cancer stem cells. This demethylation therapy shows promise as a novel treatment for advanced TGCTs.
Area of Science:
- Oncology
- Cancer Stem Cell Biology
- Epigenetics
Background:
- Testicular germ cell tumors (TGCTs) are the most common male cancers, with many patients becoming refractory to cisplatin.
- No effective therapies exist for cisplatin-refractory TGCT patients, leading to high mortality rates.
Purpose of the Study:
- To evaluate guadecitabine, a demethylating agent, for treating cisplatin-refractory TGCTs in an animal model.
- To investigate the mechanisms underlying guadecitabine's efficacy in embryonal carcinoma (EC) cells, the stem cells of TGCTs.
Main Methods:
- Utilized an animal model of cisplatin-refractory TGCTs (EC xenografts).
- Administered guadecitabine as a single agent and in combination with cisplatin.
- Performed genome-wide analysis to identify molecular pathways affected by guadecitabine.
Main Results:
- EC cells demonstrated exquisite sensitivity to guadecitabine, dependent on DNA methyltransferase 3B levels.
- Guadecitabine induced transcriptional reprogramming, including p53 target induction and pluripotency gene repression.
- Single-agent guadecitabine abolished tumor progression and induced regression of cisplatin-resistant EC xenografts.
- Low-dose guadecitabine sensitized refractory EC cells to cisplatin in vivo.
- Antitumor activity correlated with p53 and immune pathway activation, dependent on p53.
Conclusions:
- Guadecitabine is a potent single agent against cisplatin-refractory TGCTs.
- Guadecitabine demonstrates potential as a novel therapeutic strategy for refractory TGCTs, alone or combined with cisplatin.
- The findings support guadecitabine's clinical development for treating TGCT patients with refractory disease.
