Nai Jung Chiang

A KRAS mutation status-stratified randomized phase II trial of gemcitabine and oxaliplatin alone or in combination with cetuximab in advanced biliary tract cancer

BACKGROUND Previous clinical trials have not proved that adding epidermal growth factor receptor inhibitors to chemotherapy confers a survival benefit for patients with advanced biliary tract cancer (ABTC). Whether the KRAS mutation status of tumor cells confounded the results of past studies is unknown. PATIENTS AND METHODS ABTC patients stratified by KRAS status, Eastern Cooperative Oncology Group performance status, and primary tumor location were randomized 1 : 1 to receive GEMOX (800 mg/m(2) gemcitabine and 85 mg/m(2) oxaliplatin) or C-GEMOX (500 mg/m(2) cetuximab plus GEMOX) every 2 weeks. The primary end point was objective response rate (ORR). RESULTS The study enrolled 122 patients between December 2010 and May 2012 (62 treated with C-GEMOX and 60 with GEMOX). Compared with GEMOX alone, C-GEMOX was associated with trend to better ORR (27% versus 15%; P = 0.12) and progression-free survival (PFS, 6.7 versus 4.1 months; P = 0.05), but not overall survival (OS, 10.6 versus 9.8 months; P = 0.91). KRAS mutations, which were detected in 36% of tumor samples, did not affect the trends of difference in ORR and PFS between C-GEMOX and GEMOX. The two treatment arms had similar adverse events, except that more patients had skin rashes, allergic reactions, and neutropenia in the C-GEMOX arm. Of patients with C-GEMOX, the presence of a grade 2 or 3 skin rash was associated with significantly better ORR, PFS, and OS. CONCLUSIONS Addition of cetuximab did not significantly improve the ORR of GEMOX chemotherapy in ABTC, although a trend of PFS improvement was observed. The trend of improvement did not correlate with KRAS mutation status. CLINICAL TRIALS NUMBER This study is registered at ClinicalTrials.gov (NCT01267344). All patients gave written informed consent.

A Novel Synthetic Microtubule Inhibitor, MPT0B214 Exhibits Antitumor Activity in Human Tumor Cells through Mitochondria-Dependent Intrinsic Pathway

Agents that interfere with mitotic progression by disturbing microtubule dynamics are commonly used for cancer treatment. Previously, a series of aroylquinolone regioisomers as novel microtubule inhibitors were discovered. One of these new compounds, MPT0B214 inhibited tubulin polymerization through strongly binding to the tubulin’s colchicine-binding site and had cytotoxic activity in a variety of human tumor cell lines. After treatment with MPT0B214, KB cells were arrested in the G2-M phase before cell death occurred, which were associated with upregulation of cyclin B1, dephosphorylation of Cdc2, phosphorylation of Cdc25C and elevated expression of the mitotic marker MPM-2. Furthermore, the compound induced apoptotic cell death through mitochondria/caspase 9-dependent pathway. Notably, several KB-derived multidrug-resistant cancer cell lines were also sensitive to MPT0B214 treatment. These findings showed that MPT0B214 is a potential compound in the treatment of various malignancies.

Development of nanoliposomal irinotecan (nal-IRI, MM-398, PEP02) in the management of metastatic pancreatic cancer.

ABSTRACT Introduction: Systemic chemotherapy remains the standard of care for patients with advanced pancreatic ductal adenocarcinoma (PDAC). The introductions of FOLFIRINOX and nab-paclitaxel/gemcitabine combinations have improved the first-line treatment outcomes of patients with metastatic PDAC; while second-line therapy options are limited. Based on the results of pivotal NAPOLI-1 study, nanoliposomal irinotecan (nal-IRI) plus 5-fluorouracil and leucovorin (5-FU/LV) became the first US Food and Drug Administration (FDA) approved regimen for patients with metastatic PDAC with previous gemcitabine-based chemotherapy in November 2015. Areas covered: We reviewed and summarized the rationale, pharmacokinetics, therapeutic efficacy and adverse events of nal-IRI alone or combined with 5-FU/LV for metastatic PDAC with previous gemcitabine-based chemotherapy. Expert opinion: In the NAPOLI study, nal-IRI plus 5-FU/LV significantly improved the overall survival, progression-free survival and objective response rate compared to 5-FU/LV alone. The nal-IRI plus 5-FU/LV treatment was associated with a manageable toxicity profile and comparable outcomes in patients with negative demographic characteristics. The relatively sparse of neurotoxicity makes nal-IRI plus 5-FU/LV as a more favorable option than oxaliplatin-containing regimens and the current recommended standard treatment for patients with metastatic PDAC after frontline nab-paclitaxel/gemcitabine treatment. The front-line therapeutic role of nal-IRI is currently under investigation.

Epigenetic regulation in the carcinogenesis of cholangiocarcinoma

Cholangiocarcinoma (CCA) is a malignancy arising from the epithelial cells lining the biliary tract. Despite the existence of variation in incidence and etiology worldwide, its incidence is increasing globally in the past few decades. Surgery is the only curative treatment option for a minority of patients presented with early disease; while moderate effective chemotherapy remains the standard care for patients with locally advanced or metastatic diseases. In this article, we briefly review the molecular alterations that have been described in CCAs focusing on the role of epigenetic modification, including promoter methylation inactivation, histone modification and microRNA, in the carcinogenesis and progression of CCAs. This article is part of a Directed Issue entitled: Epigenetics dynamics in development and disease.

Automated selection of aptamers against cholangiocarcinoma cells on an integrated microfluidic platform

An integrated microfluidic system capable of automatically identifying aptamers specific to cholangiocarcinoma (CCA) cells was developed herein. The developed system was capable of performing cell-based systematic evolution of ligands via an exponential enrichment (Cell-SELEX) process on-chip, and only six rounds of Cell-SELEX were required to identify high specificity aptamers; this represents a significant improvement in speed over conventional SELEX, in which 15-20 rounds are typically required. Using the microfluidic chip developed, three aptamers specific to CCA cells (one for SNU-478 cells and two for HuCCT-1 cells) were successfully screened. This automated system could be modified to uncover aptamer probes against other cancer cells, thereby allowing for earlier diagnosis and consequently a potentially improved prognosis.

Expression levels of ROS1/ALK/c-MET and therapeutic efficacy of cetuximab plus chemotherapy in advanced biliary tract cancer

Aberrant expression of ROS1, ALK or c-MET (RAM) is implicated in carcinogenesis and cancer drug resistance. We retrospectively evaluated the effect of RAM expression on outcomes for advanced biliary tract cancer patients, who were treated with gemcitabine plus oxaliplatin (GEMOX), with or without cetuximab, in a randomized phase II trial. RAM expression levels on archived tissue sections were scored using immunohistochemistry (IHC). Of 110 tumors with IHC staining for all three markers, 18 were RAMhigh (IHC intensity 3+ for any markers). Ninety-two tumors were RAMlow (IHC intensity <3+ for all markers). All RAMhigh tumors were intra-hepatic cholangiocarcinomas (IHCC). Of the patients with IHCC (n = 80), median overall survival (OS) of RAMhigh group was inferior to that of the RAMlow group (5.7 vs. 11.7 months, p = 0.021). In multivariate analysis RAMhigh remained an independently adverse prognostic factor, with a hazard ratio of 2.01 (p = 0.039). In the RAMlow group, GEMOX treatment with cetuximab significantly improved the disease control rate (68% vs. 41%, p = 0.044), median progression-free survival (7.3 vs. 4.9 months, p = 0.026), and marginally prolonged median OS (14.1 vs 9.6 months, p = 0.056), compared to GEMOX treatment alone. Future trials of anti-EGFR inhibitors for IHCC may consider RAM expression as a patient stratification factor.

Stimulation of electroporation-induced inward currents in glioblastoma cell lines by the heat shock protein inhibitor AUY922

Membrane electroporation (MEP) increases the electrical conductivity of the plasma membrane by addition of an external electrical field. Combining MEP‐induced current (IMEP) with antineoplastic agents has been increasingly considered as a new therapeutic manoeuvre, especially in the treatment of malignant gliomas. Thus, the aim of the present study was to evaluate the effect of AUY922 (AUY), a potent inhibitor of heat‐shock protein 90 (HSP90), on IMEP in glioblastoma cells. The IMEP in glioblastoma cells (U373) was generated by repetitive hyperpolarization from −80 to −200 mV. The amplitude of IMEP was increased by AUY in a concentration‐dependent manner, with an EC50 of 0.32 μmol/L. In addition AUY shortened the latency to IMEP generation. Before depolarization to +50 mV, hyperpolarization to −200 mV for 50 msec produced Ca2+ influx and subsequently increased the amplitude of the Ca2+‐activated K+ current (IK(Ca)). The amplitude of IK(Ca) and Ca2+ influx was further increased by AUY through its ability to activate IMEP. Other HSP90 inhibitors, namely 17‐(allylamino)‐17‐demethoxygeldanamycin (17‐AAG; 1 μmol/L) and 6‐chloro‐9‐[(4‐methoxy‐3,5‐dimethylpyridin‐2‐yl)methyl]‐9H‐purin‐2‐amine (BIIB021; 1 μmol/L), only slightly (albeit significantly) increased the amplitude of IMEP in glioblastoma cells. A 50 msec depolarizing step elevated Ca2+ influx and subsequently increased the amplitude of IK(Ca) in the presence of these three inhibitors. These data indicate that the AUY‐mediated stimulation of IMEP and IK(Ca) in glioblastoma cells is independent of HSP90 inhibition. Moreover, these results indicate that AUY‐stimulated IMEP and the subsequent activation of IK(Ca) may create important signalling events in glioblastoma cells. Thus, AUY is a drug that could potentially be used to augment the effectiveness of electrochemotherapy.

A Microfluidic Chip for Detecting Cholangiocarcinoma Cells in Human Bile

Cholangiocarcinoma (CCA), a biliary tract malignancy, accounts for 20% of all liver cancers. There are several existing methods for diagnosis of CCA, though they are generally expensive, laborious, and suffer from low detection rates. Herein we first developed a means of partially purifying human bile for consequent injection into a microfluidic chip. Then, the novel microfluidic system, which featured 1) a cell capture module, 2) an immunofluorescence (IF) staining module featuring two CCA-specific biomarkers, and 3) an optical detection module for visualization of antibody probes bound to these CCA marker proteins, was used to detect bile duct cancer cells within partially purified bile samples. As a proof of concept, CCA cells were successfully captured and identified from CCA cell cultures, blood samples inoculated with CCA cells, and clinical bile specimens. In 7.5 ml of bile, this system could detect >2, 0, and 1 positive cells in advanced stage patients, healthy patients, and chemotherapy-treated patients, respectively. In conclusion, our microfluidic system could be a promising tool for detection of cancer cells in bile, even at the earliest stages of CCA when cancer cells are at low densities relative to the total population of epithelial cells.

An integrated microfluidic system for screening of peptides specific to cholangiocarcinoma (CCA) cancer cell lines using the phage display technology

Cholangiocarcinoma (CCA) is a cancer of bile duct, which possesses a high mortality rate and poor prognosis owing to its difficulties in early diagnosis and a lack of effective treatment. To improve the clinical detection, one of promising approaches is to find specific biomarkers to detect CCA cells. However, the existing screening processes are usually time-consuming and lab-intensive. In this study, an integrated microfluidic system was proposed to perform on-chip phage display for selection of specific peptides that could identify CCA cell lines. The results showed that we could perform one panning round within 6 hours and the whole processes could be automated. This microfluidic system may be a powerful tool for screening of affinity agents in the clinical diagnosis and target therapeutics for CCA.