Novel epi-virotherapeutic treatment of pancreatic cancer combining the oral histone deacetylase inhibitor resminostat with oncolytic measles vaccine virus.
Oncolytic viruses (OV) constitute highly promising innovative biological anticancer agents. However, like every other antitumoral compound, OV are also faced with both primary and secondary mechanisms of resistance. To overcome those barriers and moreover amplify the therapeutic potential of OV, we evaluated a novel combined approach composed of the oral histone deacetylase inhibitor resminostat and an oncolytic measles vaccine virus (MeV) for a future epi‑virotherapy of pancreatic ductal adenocarcinoma. Cytotoxicity assays revealed that combined epi-virotherapeutic treatment of four well-characterized human pancreatic cancer cell lines resulted in a beneficial tumor cell killing as compared to either monotherapeutic approach. Notably, epi-virotherapeutic treatment of MIA PaCa-2 and partly also of PANC‑1 pancreatic cancer cells resulted in a tumor cell mass reduction being significantly more pronounced than it would be expected in case of an additive effect only, indicating a synergistic mode of action when combining resminostat with MeV. We further found that the epigenetic compound resminostat neither impaired MeV growth kinetics nor prevented the activation of the interferon signaling pathway which plays an important role in mediating primary and secondary resistances to OV. Moreover, we yielded information that the pharma-codynamic function of resminostat was presumably not altered in the course of pancreatic cancer cell infections with MeV. Taken together, these promising results favor the onset of epi-viro-thera-peutic clinical trials in patients suffering from advanced pancreatic ductal adenocarcinoma.
Department of Internal Medicine I, University Hospital Tuebingen, D-72076 Tuebingen, Germany.
Tim Patrick
TP
Ellerhoff
Department of Internal Medicine I, University Hospital Tuebingen, D-72076 Tuebingen, Germany.
Susanne
S
Berchtold
Department of Internal Medicine I, University Hospital Tuebingen, D-72076 Tuebingen, Germany.
Sascha
S
Venturelli
Department of Internal Medicine I, University Hospital Tuebingen, D-72076 Tuebingen, Germany.
Markus
M
Burkard
Department of Internal Medicine I, University Hospital Tuebingen, D-72076 Tuebingen, Germany.
Irina
I
Smirnow
4SC AG, D-82152 Planegg-Martinsried, Germany.
Tanja
T
Wulff
Department of Internal Medicine I, University Hospital Tuebingen, D-72076 Tuebingen, Germany.
Ulrich M
UM
Lauer
D017209:Apoptosis; D015153:Blotting, Western; D049109:Cell Proliferation; D003131:Combined Modality Therapy; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D008458:Measles Vaccine / Q000494:pharmacology*; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses / Q000502:physiology*; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000628:therapy* / Q000821:virology; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D013449:Sulfonamides / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D014779:Virus Replication / Q000187:drug effects*
D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D008458:Measles Vaccine; D012333:RNA, Messenger; D013449:Sulfonamides; C550599:resminostat