Pancreatic cancer has one of the poorest prognoses among all
cancers partly because of its persistent resistance to
chemotherapy. The currently limited treatment options for
pancreatic cancer underscore the need for more efficient agents. Because activating Kras mutations initiate and maintain
pancreatic cancer, inhibition of this pathway should have a major therapeutic impact. We synthesized phospho-
farnesylthiosalicylic acid (PFTS; MDC-1016) and evaluated its efficacy, safety, and metabolism in preclinical models of
pancreatic cancer. PFTS inhibited the growth of human
pancreatic cancer cells in culture in a concentration- and time-dependent manner. In an MIA PaCa-2 xenograft mouse model, PFTS at a dose of 50 and 100 mg/kg significantly reduced
tumor growth by 62% and 65% (P < .05 vs vehicle control). Furthermore, PFTS prevented
pancreatitis-accelerated acinar-to-ductal
metaplasia in mice with activated Kras. PFTS appeared to be safe, with the animals showing no signs of toxicity during treatment. Following
oral administration, PFTS was rapidly absorbed, metabolized to FTS and FTS
glucuronide, and distributed through the blood to body organs. Mechanistically, PFTS inhibited Ras-
GTP, the active form of Ras, both in vitro and in vivo, leading to the inhibition of downstream effector pathways c-RAF/
mitogen-activated
protein-
extracellular signal-regulated kinase (ERK)
kinase (MEK)/ERK1/2
kinase and
phosphatidylinositol 3-kinase/AKT. In addition, PFTS proved to be a strong combination partner with phospho-
valproic acid, a novel
signal transducer and activator of transcription 3 (STAT3) inhibitor, displaying synergy in the inhibition of
pancreatic cancer growth. In conclusion, PFTS, a direct Ras inhibitor, is an efficacious agent for the treatment of
pancreatic cancer in preclinical models, deserving further evaluation.