A novel Ras inhibitor (MDC-1016) reduces human pancreatic tumor growth in mice.

Abstract

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.

• Authors: Gerardo G Mackenzie, Lauren E Bartels, Gang Xie, Ioannis Papayannis, Ninche Alston, Kvetoslava Vrankova, Nengtai Ouyang, Basil Rigas
• Journal: Neoplasia (New York, N.Y.) (Neoplasia) Vol. 15 Issue 10 Pg. 1184-95 (Oct 2013) ISSN: 1476-5586 [Electronic] United States
• PMID: 24204197 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Benzoates
• KRAS protein, human
• MDC-1112
• Organophosphates
• Proto-Oncogene Proteins
• STAT3 Transcription Factor
• phosphofarnesylthiosalicylic acid
• Valproic Acid
• Proto-Oncogene Proteins p21(ras)
• ras Proteins

Topics

• Animals
• Antineoplastic Agents (pharmacokinetics, pharmacology, therapeutic use)
• Benzoates (pharmacokinetics, pharmacology, therapeutic use)
• Cell Line, Tumor
• Drug Synergism
• Female
• Heterografts
• Humans
• Metaplasia (etiology, prevention & control)
• Mice, Inbred BALB C
• Mice, Nude
• Organophosphates (pharmacokinetics, pharmacology, therapeutic use)
• Pancreatic Neoplasms (drug therapy, pathology)
• Pancreatitis (complications, drug therapy)
• Proto-Oncogene Proteins (antagonists & inhibitors, metabolism)
• Proto-Oncogene Proteins p21(ras)
• STAT3 Transcription Factor (antagonists & inhibitors)
• Signal Transduction (physiology)
• Valproic Acid (analogs & derivatives, pharmacology)
• ras Proteins (antagonists & inhibitors, metabolism)