SAN DIEGO – The experimental drug Metavert was effective in a mouse model of aggressive pancreatic cancer, and phase I trials in humans are expected to begin in early 2017.
“Metavert significantly slows tumor growth with less toxicity in preclinical trials. The drug prevents metastasis and reduces resistance to chemotherapy. Hopefully the drug will be a good partner with other drugs,” said presenting author Mouad Edderkaoui, Ph.D., of Cedars-Sinai, Los Angeles. “We hope this drug will improve the outcome of treatment of pancreatic cancer, knowing that the drugs now available are not effective and outcome is dismal. The last drug approved for pancreatic cancer – nab-paclitaxel – extended survival by only 7 weeks.”
Dr. Mouad Edderkaoui
Dr. Edderkaoui and Dr. Stephen Pandol, director, basic and translational pancreas research, gastroenterology, at Cedars-Sinai, are cofounders of Avenzoar Pharmaceuticals, the developer of Metavert.
Metavert is a small molecular dual inhibitor that targets two procancer pathways. Preclinical results show strong prevention of pancreatic cancer growth and metastasis with no significant toxicity, according to Dr. Edderkaoui, who explained that the novel agent has two linked moieties that target the glycogen synthase kinase–3 (GSK-3) beta and histone deacetylase (HDAC).
GSK-3 beta, which is highly expressed in pancreatic cancer, stimulates proliferation and resistance to apoptosis in cancer cells. HDAC inhibits epithelial cells. In combination, the two should simultaneously affect proliferation and metastasis.
The investigators studied pancreatic cell lines and KPC mice – an animal model of aggressive pancreatic cancer that carries KRAS and p53 mutations. Metavert reduced the survival of cancer cell lines but not of normal cells.
“The [combination] drug was more potent in cell lines than the two inhibitors separately,” he said. In dose-dependent fashion, Metavert inhibited GSK-3 beta and HDAC, decreased markers of epithelial to mesenchymal transition, and decreased migration of pancreatic cancer cells.
Further, Metavert sensitized pancreatic cancer cells to chemotherapy with gemcitabine and to radiation.
In KPC mice with advanced pancreatic cancer, treatment with Metavert increased survival by about 50%. At 6 months, all control mice had died, while 42% of Metavert-treated mice were still alive.
Tumor shrinkage was observed in Metavert-treated mice. Micrometastasis was seen in 29% of controls and in none of the Metavert-treated mice.
Fibrosis was not significantly affected by treatment, and the level of M2 macrophages significantly declined in treated mice.