title: Hypomethylating therapy in an aggressive stroma-rich model of pancreatic carcinoma.
abstract: Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy that resists current treatments. To test epigenetic therapy against this cancer, we used the DNA demethylating drug 5-aza-2'-deoxycytidine (DAC) in an aggressive mouse model of stromal rich PDAC (KPC-Brca1 mice). In untreated tumors, we found globally decreased 5-methyl-cytosine (5-mC) in malignant epithelial cells and in cancer-associated myofibroblasts (CAF), along with increased amounts of 5-hydroxymethyl-cytosine (5-HmC) in CAFs, in progression from pancreatic intraepithelial neoplasia to PDAC. DAC further reduced DNA methylation and slowed PDAC progression, markedly extending survival in an early-treatment protocol and significantly though transiently inhibiting tumor growth when initiated later, without adverse side effects. Escaping tumors contained areas of sarcomatoid transformation with disappearance of CAFs. Mixing-allografting experiments and proliferation indices showed that DAC efficacy was due to inhibition of both the malignant epithelial cells and the CAFs. Expression profiling and immunohistochemistry highlighted DAC induction of STAT1 in the tumors, and DAC plus IFN-γ produced an additive antiproliferative effect on PDAC cells. DAC induced strong expression of the testis antigen deleted in azoospermia-like (DAZL) in CAFs. These data show that DAC is effective against PDAC in vivo and provide a rationale for future studies combining hypomethylating agents with cytokines and immunotherapy.
authors.affiliation: Institute for Cancer Genetics, Columbia University Medical Center, New York, New York 10032, USA.
authors.forename: Reena
authors.initials: R
authors.lastname: Shakya
authors.forename: Tamas
authors.initials: T
authors.lastname: Gonda
authors.forename: Michael
authors.initials: M
authors.lastname: Quante
authors.forename: Martha
authors.initials: M
authors.lastname: Salas
authors.forename: Samuel
authors.initials: S
authors.lastname: Kim
authors.forename: Jenna
authors.initials: J
authors.lastname: Brooks
authors.forename: Steffen
authors.initials: S
authors.lastname: Hirsch
authors.forename: Justine
authors.initials: J
authors.lastname: Davies
authors.forename: Angelica
authors.initials: A
authors.lastname: Cullo
authors.forename: Kenneth
authors.initials: K
authors.lastname: Olive
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Wang
authors.forename: Matthias
authors.initials: M
authors.lastname: Szabolcs
authors.forename: Benjamin
authors.initials: B
authors.lastname: Tycko
authors.forename: Thomas
authors.initials: T
authors.lastname: Ludwig
mesh_terms: D000818:Animals; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D019175:DNA Methylation / Q000187:drug effects*; D000077209:Decitabine; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D017154:Stromal Cells / Q000473:pathology
chemical_list: D000077209:Decitabine; D001374:Azacitidine