Chemovirotherapy employing Gemcitabine together with Oncolytic Measles Vaccine Viruses as a new Option for the Treatment of Pancreatic Cancer

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Dokumentart: PhDThesis
Date: 2020-08-13
Language: English
Faculty: 4 Medizinische Fakultät
Department: Medizin
Advisor: Lauer, Ulrich (Prof. Dr.)
Day of Oral Examination: 2020-07-14
DDC Classifikation: 610 - Medicine and health
Keywords: Bauchspeicheldrüsenkrebs
Other Keywords:
oncolytic virotherapy
pancreatic cancer
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Current therapeutic options for locally advanced or metastatic pancreatic cancer still are not able to improve the prognosis of patients long-lasting. Thus, it is more than urgent to find new strategies to overcome therapeutic resistance and inefficiency, respectively, by establishing novel combinatorial approaches encompassing new therapeutic principles. “Oncolytic virotherapy with vaccine viruses employs replicative vectors, which quite selectively infect tumor cells leading to massive virus replication followed by subsequent profound tumor cell death (oncolysis). Measles vaccine virus (MeV) has already shown great oncolytic activity against different types of cancers, including pancreatic cancer. Gemcitabine is a first line chemo-therapeutic drug used for pancreatic cancer in palliative treatment plans. Furthermore, this drug can be used to induce senescence, a permanent cell cycle arrest, in tumor cells. In our preclinical work, three well-characterized immortalized human pancreatic cancer cell lines were used to investigate the combinatorial effect of MeV-based virotherapy together with the chemo-therapeutic compound gemcitabine. Viability assays revealed that the combination of only small amounts of MeV together with subtherapeutic concentrations of gemcitabine resulted in a tumor cell mass reduction of > 50%. To further investigate the replication of the oncolytic MeV vectors under these distinct combinatorial conditions, viral growth curves were generated. As a result, viral replication was found to be only slightly diminished in the presence of gemcitabine. As gemcitabine induces senescence, the effect of MeV on that phenomenon was explored using a senescence-associated β-galactosidase assay. Notably, gemcitabine-induced tumor cell senescence was not impaired by MeV. Accordingly, the chemovirotherapeutic combination of gemcitabine plus oncolytic MeV constitutes a novel therapeutic option for advanced pancreatic carcinoma that is characterized by the mutual improvement of the effectiveness of each therapeutic component.“

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