A novel chemotherapeutic agent, the highly selective MEK1/2 inhibitor BAY 86-9766, may be a promising future treatment for pancreatic ductal adenocarcinoma (PDAC), according to preclinical results presented at the American Association for Cancer Research’s Pancreatic Cancer: Progress and Challenges conference.
“We showed in our endogenous mouse model that our novel chemotherapeutic agent leads to dramatic tumor shrinkage after only one week of treatment,” said Nicole Teichmann, Ph.D., of the Klinikum rechts der Isar at the Technische Universität München in Munich, Germany. “Moreover, the therapy was as effective in animals with advanced tumors and ascites, which is often the case if patients come to the clinic.”
In this preclinical therapeutic study, BAY 86-9766 was evaluated in one of the most aggressive mouse models for PDAC, according to Teichmann. The researchers induced endogenous genetic alterations in these mice, and within eight weeks, the mice developed invasive, lethal PDAC. These genetic alterations closely mimic what is found in most human cases of the disease, she said.
“The mutations trigger the onset of a signaling cascade that is necessary for the survival and proliferation of the cancer cells,” Teichmann said. “Our novel chemotherapeutic drug inhibits one essential protein of this cascade and therefore leads to the cascade’s shutdown.”
A daily treatment of 25 mg/kg with BAY 86-9766 prolonged the survival of the mice in the study compared to their ‘placebo’-treated counterparts; median survival advantage was 20 days. The treatment caused dramatic tumor regression after only one week and was effective in animals with advanced tumors and ascites, which is often how patients present to the clinic.
“We were really surprised that the tumor load dramatically decreases after one week of therapy and also that the treatment conferred such a strong overall survival benefit,” Teichmann said. “Previous studies with gemcitabine, the standard-of-care agent for PDAC 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 PDAC.”
In most animals, the tumor relapsed after three weeks of treatment, which modeled the situation in humans. “Often patients respond to a therapy and after a while, the tumor relapses,” she added. “We can exploit this same tumor relapse in the mouse to investigate the resistance mechanism to improve the therapeutic strategy.”
These findings encourage testing in mouse models rather than xenograft models. “Our 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,” Teichmann said.
MEK1/2 inhibition with the novel chemotherapeutic agent BAY 86-9766 (RDEA119) – a promising treatment strategy for pancreatic cancer. Nicole Teichmann1, Marija Trajkovic-Arsic1, Arne Scholz2, Schmid M. Roland1, Braren Rickmer1, Jens T. Siveke1. 1Klinikum rechts der Isar, Technische Universität München, Munich, Germany, 2Bayer Schering Pharma AG, Berlin, Germany.
American Association for Cancer Research