This translational study program has integrated basic scientists and clinical investigators of NICR and NCKUH to dissect pancreatic cancer (PDAC) from various aspects including case-controlled epidemiological study, basic and translational research focused on drug resistance, cancer stem cells, metabolism, microenvironment, and their interactions, and clinical trials. We have built 3D tissuemimetic model, zebrafish dissemination model, and orthotopic xenograft and transgenic mouse models for preclinical research, and also collected clinical samples from our collaborators in NCKUH and clinical trials to support this program.
One of the most exciting achievement of NICR in the past years is the success of a global, randomized phase III NAPOLI-1 trial to show the superiority of liposomal irinotecan+5-FU/LV (nal-IRI, MM-398, PEP02) compared to 5-FU/LV alone in prolong the survival of patients with metastatic PADC after previous gemcitabine-based chemotherapy [Lancet, 2016]. We have worked on this compound with PharmaEngine for 10 years to achieve this goal. Started from the first-in-human phase I trial of PEP02 to a dose finding phase Ib study for PEP02 in combination with weekly 24-hour infusion of high-dose 5-FU/LV, and followed by an international study (NHRI/NCKUH, NTUH and UCSF) phase II trial to demonstrate the activity of PEP02 in second-line therapy for gemcitabine-refractory PDAC [Cancer Chemother Pharmacol, 2015; BMC Cancer, 2016; Br J Cancer, 2013], PharmaEngine was able to license the compound out to an US company, the Merrimack, in 2011, which made NAPOLI-1 study possible in January 2012. The positive results of NAPOLI-1 led to the approval for the use of nal-IRI+5-FU/LV as the second-line therapy in gemcitabine-based chemotherapy failed metastatic PDAC by US FDA, Taiwan FDA, EMEA, Canada and Korea. Furthermore, this treatment was included in National Comprehensive Cancer Network® (NCCN®), ESMO and ASCO Guideline in 2016. ONIVYDETM (MM-398, PEP02) is the first FDA approved cancer drug that begins its clinical development in Taiwan.
In preclinical studies, based on those well-established infrastructure and resources, Dr. KK Tsai have successfully developed a 28-gene “tubulogenesis-specific signature”, which can accurately predict the survival of patients with pancreatic cancer better than traditional clinical and pathologic criteria and previously reported gene signatures.[ROC patent, 2016] One of top listed gene in the signature, abnormal spindle-like microcephaly associated (ASPM) is a novel positive regulator of the Wnt signaling pathway and associated with PDAC cancer stemness and tumor aggressiveness [Gastroenterology 2013], as it does in prostate cancer, glioblastoma and NSCLC. This is the first study to link tissue architecture associated molecular pattern with the clinical behavior of PDAC. The study illustrates that biology-informed molecular markers can greatly enhance outcomes prediction in malignant tumors and provide valuable diagnostic and therapeutic information.
Dr. HJ Ch’ang has identified low expression level of KLF10 (Krüppel- like factor 10), as an independent adverse prognostic factor for patients with PDAC after curative resection [Am J Pathol 2012]. Data from her lab suggested that Klf10 may transcriptionally suppresses the expression level of ultraviolet irradiation resistance-associated gene (UVRAG) so as to modulate autophagy, apoptosis and DNA damage repair after radiation and thus the radio-sensitivity of PDAC cells. The predictive value of Klf10 in radiation response and the inverse correlation with UVRAG were confirmed in cohorts of pancreatic cancer patients. [Radiother Oncol.2017] Dr. Ch’ang and Dr. Winston CY YU, have identified KLF10 as a phosphorylated protein in cells through in vivo and in vitro phosphorylation assays, and RAF-1 phosphorylation and PIN1 isomerization together regulate KLF10 stability and further affect the role of KLF10 in tumor progression. [Biochim Biophys Acta 2013]. In addition, Dr. LT Chen and Dr. KH Cheng generated a Pdx-1-Cre LSL-KrasG12DKLF10L/Lp53L/L (PKKP) to demonstrate loss of KLF10 in PDAC can increase distant metastases and cancer stemness through activation of SDF-1/CXCR4 and AP-1 pathways. Targeting the SDF-1/CXCR4 pathway in the context of KLF10 deletion can substantially suppress PDAC progression [Oncogene 2017].