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

Gerardo Mackenzie, Lauren E. Bartels, Gang Xie, Ioannis Papayannis, Ninche Alston, Kvetoslava Vrankova, Nengtai Ouyang, Basil Rigas

Research output: Contribution to journalArticle

17 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1184-1195
Number of pages12
JournalNeoplasia (United States)
Volume15
Issue number10
DOIs
StatePublished - Jan 1 2013
Externally publishedYes

    Fingerprint

ASJC Scopus subject areas

  • Cancer Research

Cite this

Mackenzie, G., Bartels, L. E., Xie, G., Papayannis, I., Alston, N., Vrankova, K., Ouyang, N., & Rigas, B. (2013). A novel Ras inhibitor (MDC-1016) reduces human pancreatic tumor growth in mice. Neoplasia (United States), 15(10), 1184-1195. https://doi.org/10.1593/neo.131368