Refractory testicular germ cell tumors are highly sensitive to the second generation DNA methylation inhibitor guadecitabine
| Autor: | Sarah E. Bock, Janice Tam, George E. Sandusky, Brian S. Curran, Mary P. Hever-Jardine, Joshua M. Warzecha, Fred Kim, Michael J. Spinella, Costantine Albany, Aneeq S. Chaudhry, Katherine M. von Herrmann, Lawrence H. Einhorn, Sarah J. Freemantle, Brock C. Christensen, Leah Shin, Christina Y. Yim, Pietro Taverna |
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| Rok vydání: | 2016 |
| Předmět: |
embryonal carcinoma
Male 0301 basic medicine Somatic cell DNA Methyltransferase Inhibitor Antineoplastic Agents Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Testicular Neoplasms Cell Line Tumor medicine Animals Humans DNA (Cytosine-5-)-Methyltransferases Testicular cancer Cisplatin DNA methylation business.industry Gene Expression Profiling Neoplasms Germ Cell and Embryonal medicine.disease Xenograft Model Antitumor Assays testicular cancer Demethylating agent Gene Expression Regulation Neoplastic in vivo 030104 developmental biology Oncology chemistry Drug Resistance Neoplasm 030220 oncology & carcinogenesis SGI-110 Immunology Azacitidine Cancer research Tumor Suppressor Protein p53 Stem cell business Reprogramming Research Paper medicine.drug |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| DOI: | 10.18632/oncotarget.13811 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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