DNA methyltransferase 1 (DNMT1) is scientifically validated as a molecular target to treat chemo-resistant pancreatic ductal
adenocarcinoma (PDAC). Results of clinical studies of the
pyrimidine nucleoside analog decitabine to target DNMT1 in PDAC have, however, disappointed. One reason is high expression in PDAC of the
enzyme cytidine deaminase (CDA), which catabolizes
decitabine within minutes. We therefore added
tetrahydrouridine (THU) to inhibit CDA with
decitabine. In this pilot clinical trial, patients with advanced chemorefractory PDAC ingested oral THU ~10 mg/kg/day combined with oral
decitabine ~0.2 mg/kg/day, for 5 consecutive days, then 2X/week. We treated 13 patients with extensively metastatic chemo-resistant PDAC, including 8 patients (62%) with
ascites: all had received ≥ 1 prior
therapies including
gemcitabine/
nab-paclitaxel in 9 (69%) and
FOLFIRINOX in 12 (92%). Median time on THU/
decitabine treatment was 35 days (range 4-63). The most frequent treatment-attributable adverse event was
anemia (n=5). No deaths were attributed to THU/
decitabine. Five patients had clinical progressive disease (PD) prior to week 8. Eight patients had week 8 evaluation scans: 1 had stable disease and 7 PD. Median overall survival was 3.1 months.
Decitabine systemic exposure is expected to decrease neutrophil counts; however,
neutropenia was unexpectedly mild. To identify reasons for limited systemic
decitabine effect, we measured plasma CDA
enzyme activity in PDAC patients, and found a > 10-fold increase in those with metastatic vs resectable PDAC. We concluded that CDA activity is increased not just locally but also systemically in metastatic PDAC, suggesting a need for even higher CDA-inhibitor doses than used here.