Oncotarget

Research Papers:

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 E. Sandusky, Pietro Taverna, Sarah J. Freemantle, Brock C. Christensen, Lawrence H. Einhorn and Michael J. Spinella _

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Oncotarget. 2017; 8:2949-2959. https://doi.org/10.18632/oncotarget.13811

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Abstract

Costantine Albany1, Mary P. Hever-Jardine2, Katherine M. von Herrmann2, Christina Y. Yim2, Janice Tam2, Joshua M. Warzecha2, Leah Shin2, Sarah E. Bock2, Brian S. Curran2, Aneeq S. Chaudhry2, Fred Kim2, George E. Sandusky5, Pietro Taverna3, Sarah J. Freemantle4, Brock C. Christensen6, Lawrence H. Einhorn1, Michael J. Spinella4

1Division of Hematology/Oncology, Melvin and Bren Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN, USA

2Departments of Pharmacology and Toxicology and Epidemiology, Geisel School of Medicine at Dartmouth, Hanover, NH, USA

3Astex Pharmaceutical, Pleasanton, CA, USA

4Department of Comparative Biosciences, The University of Illinois at Urbana-Champaign, Urbana, IL, USA

5Department of Pathology, Melvin and Bren Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN, USA

6Department of Epidemiology, Geisel School of Medicine at Dartmouth, Hanover, NH, USA

Correspondence to:

Michael J. Spinella, email: [email protected]

Keywords: testicular cancer, embryonal carcinoma, DNA methylation, SGI-110, in vivo

Received: October 20, 2016     Accepted: November 23, 2016     Published: December 07, 2016

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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