Effect of Telomerase Peptide Vaccination, GV 1001 Combined with Gemcitabine in Treatment of Pancreatic Ductal Adenocarcinoma

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의과대학 의학과
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서울대학교 대학원
GV 1001Gemcitabinexenograft tumor modelpancreatic ductal adenocarcinoma
학위논문 (박사)-- 서울대학교 대학원 : 의학과, 2014. 8. 이왕재.
Introduction: Pancreatic ductal adenocarcinoma (PDAC) shows dismal prognosis due to early metastasis, frequent recurrence and chemo-resistance. However, there is no effective treatment to overcome these problems. GV1001 is a telomerase-based cancer vaccine made of a 16-mer TERT peptide and human telomerase reverse transcriptase (hTERT), the rate-limiting subunit of the telomerase complex, is therefore an attractive target for cancer vaccination. The aim of this study was to evaluate the combination benefit of telomerase peptide vaccination, GV1001 combined with gemcitabine in PDAC.
Methods: Human pancreatic cancer cell lines (Panc-1 and AsPC-1) were used in vitro experiment and also, PDAC xenograft mice model was established using pancreatic cancer cell lines (Panc-1 and AsPC-1). Treatment groups were divided as follows
control, gemcitabine alone, GV 1001 alone, gemcitabine and GV 1001 combination. The changes of weight and tumor size were evaluated in regular intervals before and after the treatment. The inflammatory cytokines (IL-1β, IL-6, TNF-α, INF-γ), leptin and ghrelin were measured from the serum of xenograft tumor mice model.
In vitro experiments: GV1001 treatment alone did not affect the proliferation or the apoptosis of PDAC cells.
In vivo experiments: Mean tumor volume and size were decreased in treatment of gemcitabine alone group and gemcitabine with GV 1001 group, and there were no significant differences between the two groups. However, gemcitabine alone or gemcitabine with GV 1001 treatment groups had significantly small tumor size and volume compared to control group (P < 0.001). Interestingly, there was a significant difference in mean body weight between the groups with gemcitabine alone vs. gemcitabine with GV 1001 combination groups. Mice of gemcitabine with GV 1001 treatment group did not have significant weight loss compared to gemcitabine alone group although they have decreased tumor size and volume. Serum level of IL-1β showed significant decrease in groups with GV1001 combination with gemcitabine and GV1001 only (p=0.01). On the other hands, serum level of IFN –γ and TNF-α significantly increased in groups with GV1001 including treatment (p<0.001). Treatment groups with gemcitabine alone and gemcitabine combined with GV1001 had significant amount of reduced tumor size and abundant apoptosis from the evaluation of xenograft tumor specimens after the sacrifice. Surprisingly, xenograft tumor tissue in gemcitabine single treatment group showed tumor tissue had been replaced by severe fibrosis whereas gemcitabine combined with GV1001 treatment group had significant reduced fibrosis.
Conclusions: GV1001 showed beneficial effects combined with gemcitabine in PDAC xenograft mice model preventing from emaciation. Moreover, GV 1001 combined with gemcitabine treatment showed significant loss of fibrosis in tumor tissue as well as tumor cell death. Therefore, further investigation of GV1001 effect may give us useful insights to understand the biology of PDAC progression and the synergistic effects of anti-cancer drug delivery in PDAC treatment.
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College of Medicine/School of Medicine (의과대학/대학원)Dept. of Medicine (의학과)Theses (Ph.D. / Sc.D._의학과)
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