Exploration of New Treatment in Advanced Pancreatic Cancer

• Main Authors: Shih-Hung Yang, 楊士弘
• Other Authors: Kun-Huei Yeh
• Format: Others
• Language: zh-TW
• Published: 2019
• Online Access: http://ndltd.ncl.edu.tw/handle/3tf46y

博士 === 國立臺灣大學 === 臨床醫學研究所 === 107 === Pancreatic cancer is highly lethal with great medical unmet needs. The majority of patients have adenocarcinoma. The 5-year overall survival (OS) rate is 5%. At initial diagnosis, only 20% of patients have resectable diseases. Gemcitabine and 5-FU/5-FU analogs are the mostly utilized agents until recent years with low response rate (RR). The standard first-line combination chemotherapy regimens, such as FOLFIRINOX or gemcitabine plus nab-paclitaxel, are associated with significant toxicities. The development of targeted therpy is quite limited. The only approved drug is erlotinib with minimal OS benefit. Good local control can be achieved with radiotherapy (RT). However, the role of RT in advanced pancreatic cancer is under debate. TP53 is mutated in 70% of pancreatic cancer. The dysfunction of p53 is associated with dysregulated cell cycle, apoptosis, and senescence. MDM2 is the major negative regulator of p53, functions both as an E3 ubiquitin ligase and an inhibitor of p53 transactivation. In addition, MDM2 also regulates p53-independent pro-survival signaling in cancer cells. Gemcitabine, a nucleoside analog, works by blocking DNA replication and inducing DNA breaks, which results in cell death. Other investigators found that the resistance of gemcitabine was probably associated with defective p53-associated pathways. The functional intactness of the MDM2-p53 loop may be defective in pancreatic cancer. Therefore, MDM2 may be also implicated in the resistance of gemcitabine. To explore the implication of MDM2-p53 loop in clinical setting and in vitro study may provide us important clues for development of targeted therapy in pancreatic cancer. This thesis included two themes. These studies were described as follows: Based on the hypothesis that both of MDM2 and p53 are implicated with the resistance of gemcitabine, the retrospective study (Study 1) was proposed. Patients with complete medical records, imaging data and histopathologic diagnosis of pancreatic adenocarcinoma were selected. Archival tissues and prior exposure to gemcitabine-based chemotherapy for pancreatic cancer were required. Formalin-fixed, paraffin-embedded tumor tissue sections were stained with immunohistochemistry. When at least 10% of the tumor cells had positive staining, MDM2 and p53 expression were considered positive. As a result, expression of MDM2 and p53 was found in 21.9% and 51.8% patients, respectively. MDM2 was significantly associated with poor prognosis (median OS 3.7 vs 5.8 months, P = .048), while p53 had no prognostic significance. MDM2 but not p53 was significantly associated with progressive disease or death after first-line gemcitabine-based chemotherapy. In addition, MDM2 but not p53 expression was significantly associated with high C-reactive protein (CRP) level at initial diagnosis. Following the clinical finding of MDM2, in vitro cell line study of pancreatic adenocarcinoma (Study 2) was performed to explore the mechanism of MDM2-associated poor prognosis. Among the cell lines, the baseline expression of ribonucleotide reductase regulatory subunit M2, deoxycytidine kinase, RelA/p65, p53, p21, MDM2, and MDM4/MDMX was not associated with gemcitabine sensitivity. Panc-1, a cell line with MDM2 expression and TP53 mutation, was moderately resistant to gemcitabine (IC50: 1.17±0.30 μM, 72-hr MTT assay). After transient tranfection of MDM2 DNA plasmid and short-term (30 mins) exposure to gemcitabine in the clonogenic assay, gemcitabine resistance was demonstrated with increased colonies in Panc-1 cells with MDM2 overexpression. To explore the role of radiotherapy in advanced pancreatic cancer, the retrospective study (Study 3) about the utilization of radiotherapy was proposed. The median OS was significantly better in patients with RT than those without it (14.6 vs. 8.1 months, P < .001). The choice of RT in pancreatic cancer for first-line therapy was significantly associated with initial stage and CA 19-9 level. Obviously, the retrospective study, which was limited to potential bias from patient selection and tumor burden, remained inconclusive. To explore the clinical feasiblity of RT combined with S-1, the phase I study (Study 4) was proposed to use S-1-based, short-course and low-dose RT followed by gemcitabine plus S-1 (GS) in metastatic pancreatic cancer. The 3+3 trial design was adopted. First, patients received concurrent chemoradiotherapy (CCRT) with RT (2.5–3.6 Gy/day for 10–12 fractions) and S-1 (50–70 mg/m2/day). After a short rest, gemcitabine (1000 mg/m2 on days 1 and 15) and S-1 (60–100 mg/day on days 1–7 and 15–21), were administered in a 4-week cycle. The primary endpoint was the maximum tolerated dose (MTD) and safety profiles of CCRT. As a result, the MTD of CCRT was not identified due to the slow recruitment and premature termination. Ten patients were enrolled. In the CCRT part, hematological toxicity was mild. The most common non-hematological toxicities were mild gastrointestinal upsets. The local disease-control rate (DCR) was 100% after CCRT. Palliation was significant with the pain control rate of 56%, free-from-bowel obstruction rate of 90%, and new biliary obstruction rate of 17%. The median OS was 9.8 (95%CI, 7.3-12.4) months. These results demonstrated that S-1-based CCRT was tolerable in metastatic pancreatic cancer with manageable toxicities. In summary, MDM2 but not p53 expression in pancreatic tumor tissues was associated with poor prognosis and disease progression. MDM2 overexpression was associated with in vitro gemcitabine resistance. In the future exploration, enhancement of gemcitabine efficacy through inhibition of MDM2 may shed light on the therapy in advanced pancreatic cancer