MEK1/2 inhibition with the novel chemotherapeutic agent
Novel chemotherapy agent shows promise in a preclinical model that mimics molecular and morphological characteristics of human pancreatic ductal adenocarcinoma
- Date : 28 Jun 2012
- Topic : Gastrointestinal cancers
A novel chemotherapeutic agent, the highly selective MEK1/2 inhibitor BAY 86-9766, may be a promising in pancreatic ductal adenocarcinoma, according to preclinical results presented at the American Association for Cancer Research's Pancreatic Cancer: Progress and Challenges conference, held in Lake Tahoe, USA (June 18-21, 2012).
To mimic molecular and morphological characteristics of human pancreatic ductal adenocarcinoma, the researchers generated mice with pancreas specific activation of oncogenic KRAS and concomitant deletion of p53. These genetic alterations closely mimic what is found in most human cases of the disease. Those mice develop invasive pancreatic ductal adenocarcinoma and typically die at 8 weeks of age. To assess the in vivo efficacy of BAY 86-9766, mice with a defined tumour burden were treated daily with 25 mg/kg of BAY 86-9766 from 40 days of age until death. Tumour progression was monitored by measurements of tumour volume via non-invasive T2-weighted magnetic resonance imaging.
Taking into account the genetic and morphological heterogeneity of the disease
In their endogenous mouse model the researchers led by Nicole Teichmann, PhD of the Technical University in Munich, Germany, have showed that novel chemotherapeutic agent led to dramatic tumour shrinkage after only one week of treatment. Moreover, the therapy was as effective in animals with advanced tumours and ascites, which is often the case if patients come to the clinic.
The mutations trigger the onset of a signalling cascade that is necessary for the survival and proliferation of the cancer cells. Novel chemotherapeutic drug inhibits one essential protein of this cascade and therefore leads to the cascade's shut-down.
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 tumour regression after only one week and was effective in animals with advanced tumours and ascites, which is often how patients present to the clinic.
Previous studies with gemcitabine, the standard-of-care agent for pancreatic ductal adenocarcinoma since 1997, or other novel inhibitors tested in lab with the same mouse model showed no or only very modest effects. This is the first targeted drug to have shown such strong tumour effects in an endogenous mouse model of pancreatic ductal adenocarcinoma.
In most animals, the tumour relapsed after three weeks of treatment, which modelled the situation in humans. The researchers can exploit this same tumour relapse in the mouse to investigate the resistance mechanism to improve the therapeutic strategy.
The 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.
These preclinical data provide compelling evidence that the novel MEK1/2 inhibitor BAY 86-9766 is a promising agent. The continuing profound examination of the escape mechanism of the relapsing tumour can then be exploited to develop an improved therapy strategy for this aggressive cancer type in the future.
Thank you for rating!
You have already rated this page, you can only rate it once!