Refractory testicular germ cell tumors are highly sensitive to the second generation DNA methylation inhibitor guadecitabine

Costantine Albany, Mary P. Hever-Jardine, Katherine M. von Herrmann, Christina Y. Yim, Janice Tam, Joshua M. Warzecha, Leah Shin, Sarah E. Bock, Brian S. Curran, Aneeq S. Chaudhry, Fred Kim, George Sandusky, Pietro Taverna, Sarah J. Freemantle, Brock C. Christensen, Lawrence Einhorn, Michael J. Spinella

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)2949-2959
Number of pages11
JournalOncotarget
Volume8
Issue number2
DOIs
StatePublished - 2017

Fingerprint

DNA Methylation
Embryonal Carcinoma Stem Cells
Cisplatin
Embryonal Carcinoma
Deoxycytidine
Testicular Germ Cell Tumor
SGI-110
p53 Genes
Testicular Neoplasms
Methyltransferases
Heterografts
Neoplasms
Hypersensitivity
Animal Models
Genome
DNA
Therapeutics
Genes

Keywords

  • DNA methylation
  • Embryonal carcinoma
  • In vivo
  • SGI-110
  • Testicular cancer

ASJC Scopus subject areas

  • Oncology

Cite this

Albany, C., Hever-Jardine, M. P., von Herrmann, K. M., Yim, C. Y., Tam, J., Warzecha, J. M., ... Spinella, M. J. (2017). Refractory testicular germ cell tumors are highly sensitive to the second generation DNA methylation inhibitor guadecitabine. Oncotarget, 8(2), 2949-2959. https://doi.org/10.18632/oncotarget.13811

Refractory testicular germ cell tumors are highly sensitive to the second generation DNA methylation inhibitor guadecitabine. / Albany, Costantine; Hever-Jardine, Mary P.; von Herrmann, Katherine M.; Yim, Christina Y.; Tam, Janice; Warzecha, Joshua M.; Shin, Leah; Bock, Sarah E.; Curran, Brian S.; Chaudhry, Aneeq S.; Kim, Fred; Sandusky, George; Taverna, Pietro; Freemantle, Sarah J.; Christensen, Brock C.; Einhorn, Lawrence; Spinella, Michael J.

In: Oncotarget, Vol. 8, No. 2, 2017, p. 2949-2959.

Research output: Contribution to journalArticle

Albany, C, Hever-Jardine, MP, von Herrmann, KM, Yim, CY, Tam, J, Warzecha, JM, Shin, L, Bock, SE, Curran, BS, Chaudhry, AS, Kim, F, Sandusky, G, Taverna, P, Freemantle, SJ, Christensen, BC, Einhorn, L & Spinella, MJ 2017, 'Refractory testicular germ cell tumors are highly sensitive to the second generation DNA methylation inhibitor guadecitabine', Oncotarget, vol. 8, no. 2, pp. 2949-2959. https://doi.org/10.18632/oncotarget.13811
Albany, Costantine ; Hever-Jardine, Mary P. ; von Herrmann, Katherine M. ; Yim, Christina Y. ; Tam, Janice ; Warzecha, Joshua M. ; Shin, Leah ; Bock, Sarah E. ; Curran, Brian S. ; Chaudhry, Aneeq S. ; Kim, Fred ; Sandusky, George ; Taverna, Pietro ; Freemantle, Sarah J. ; Christensen, Brock C. ; Einhorn, Lawrence ; Spinella, Michael J. / Refractory testicular germ cell tumors are highly sensitive to the second generation DNA methylation inhibitor guadecitabine. In: Oncotarget. 2017 ; Vol. 8, No. 2. pp. 2949-2959.
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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.",
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AU - Hever-Jardine, Mary P.

AU - von Herrmann, Katherine M.

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AU - Tam, Janice

AU - Warzecha, Joshua M.

AU - Shin, Leah

AU - Bock, Sarah E.

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AU - Kim, Fred

AU - Sandusky, George

AU - Taverna, Pietro

AU - Freemantle, Sarah J.

AU - Christensen, Brock C.

AU - Einhorn, Lawrence

AU - Spinella, Michael J.

PY - 2017

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N2 - 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.

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