MEK1/2 Inhibitor BAY 86-9766 Prolongs Survival in Mouse Model of Pancreatic Ductal Adenocarcinoma

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(ChemotherapyAdvisor) – The novel, highly selective MEK1/2 inhibitor BAY 86-9766 “is a promising future therapeutic agent for the treatment of pancreatic cancer,” according to “compelling” preclinical data presented June 20 at the American Association for Cancer Research's Pancreatic Cancer: Progress and Challenges conference, Lake Tahoe, NV.

The study used a genetically engineered mouse model of pancreatic ductal adenocarcinoma that mimicked molecular and morphological characteristics of the disease, noted Nicole Teichmann, PhD, of the Klinikum rechts der Isar at the Technische Universität München, Munich, Germany. Specifically, “we generated mice with pancreas-specific activation of oncogenic K-ras and concomitant deletion of p53 (Ptf1a+/Cre, K-ras+/LSL-G12D, p53loxP/loxP; CKP) using a Cre/loxP approach.” Typically, such mice develop invasive pancreatic cancer and die at 8 weeks of age.

Mice with a defined tumor burden were treated with BAY 86-9766 25mg/kg/day from 40 days of age until death. Tumor progression was monitored by measurements of tumor volume via non-invasive T2-weighted magnetic resonance imaging on a clinical 1,5T MRI device.

BAY 86-9766 was found to prolong survival significantly, with a median survival advantage of 20 days. “Dramatic” tumor regression was observed after 1 week of treatment, Dr. Teichmann reported.

“This strong decrease of the tumor load was also seen when therapy was applied in mice with advanced tumors and ascites,” she added. In most animals, tumors relapse after 3 weeks of treatment and, in these animals, the tumors presented with altered morphological features vs vehicle-treated controls.

“Previous studies with gemcitabine, the standard-of-care agent for pancreatic ductal adenocarcinoma since 1997, or other novel inhibitors tested in our lab with the same mouse model showed no or only very modest effects. In our hands, this is the first targeted drug to have shown such strong tumor effects in an endogenous mouse model of pancreatic ductal adenocarcinoma,” Dr. Teichmann said.

Primary mouse pancreatic tumor cell lines from vehicle and BAY 86-9766-treated pancreatic ductal adenocarcinoma were established and further characterized. An epithelial to mesenchymal transition (EMT) phenotype was observed in some cell lines isolated from mice treated with BAY 86-9766 and only 1 cell line isolated from vehicle-treated controls.

“These data suggest that BAY 86-9766 treatment induced EMT, which coincides with the histological analysis and concomitant lower sensitivity to erlotinib treatment,” she reported. “Moreover, those cells exhibited higher protein levels of p-EGFR and p-ERK as well as higher mRNA and active GTP-bound levels of the driving oncogene K-ras, which could be involved in triggering EMT.”

These results support testing novel agents for pancreatic cancer in endogenous mouse models, rather than conventional xenograft models “because they take into account the genetic and morphological heterogeneity of the disease and may be more predictive with regard to efficacy,” Dr. Teichmann concluded.

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