12 Feb Identifying Gene Expression of Early Lung Cancer Exposes More Drug Targets
MedicalResearch.com Interview with:
Dr. Chiara Ambrogio
Chiara Ambrogio, PhD
Experimental Oncology Group
CNIO-Centro Nacional de Investigaciones Oncológicas
(Spanish National Cancer Research Centre)
Melchor Fernández Almagro nº3
Madrid Spain
Medical Research: What is the background for this study?
Dr. Ambrogio: The majority of preclinical studies aimed at discovering new therapeutic strategies for lung adenocarcinoma have been conducted so far in full-blown tumors. We wanted to try a new approach by studying early lung lesions in a KRasG12V mouse model in order to bypass the problems imposed by tumor heterogeneity in later stages of the disease. We reasoned that the analysis of the first steps of lung adenocarcinoma development would help us in identifying valuable targets for therapeutic intervention.
Medical Research: What are the main findings?
Dr. Ambrogio:
1) We performed gene expression analysis of KRasG12V-driven mouse lung hyperplasias (≤ 500 cells) and we compared it to the gene expression profile of full-blown lung adenocarcinoma. We found that the aggressive nature of this tumor type is determined earlier than what predicted by histopathological criteria.
2) The analysis of transcriptional changes in early lesions allowed us to identify DDR1 as a drugable target in KRasG12V-driven lung adenocarcinoma. We validated its potential as a therapeutic target both genetically and pharmacologically by means of a selective DDR1 inhibitor. We demonstrated that the co-inhibition of DDR1 and NOTCH pathway, a key player in DDR1-mediated survival, exerted additive therapeutic effect.
3) We confirmed these results in human lung adenocarcinoma by reporting, for the first time, the development of an orthotopic Patient-Derived Xenograft (PDX) model as the ideal platform for the preclinical evaluation of new therapeutic strategies.
Medical Research: What should clinicians and patients take away from your report?
Dr. Ambrogio:
1) There is an urgent need for more accurate patient stratification. Personalized medicine is becoming a real possibility, and the better we characterize individual tumors the greater the chances we have to treat them efficiently.
2) In the attempt to give to our results a truly translational value, we used for the PDX experiments drugs that were either FDA approved or close to approval. We went as far as we could with preclinical approximation in a cancer research institute, now the best future perspective would be passing the baton to clinicians to start a Phase I clinical trial with human patients.
Medical Research: What recommendations do you have for future research as a result of this study?
Dr. Ambrogio: We envision two lines of investigation that can be developed following our results. The first one is to validate other potential therapeutic targets that emerged from the gene expression analysis of early lung lesions.
The second one is testing whether our therapeutic approach is efficient also in lung adenocarcinoma driven by mutations other than KRas.
As a general recommendation, we would like to deliver the message that a similar approach can be conducted in any type of solid tumor with an appropriate mouse model. Looking for new therapeutic targets studying early lesions will be extremely informative also in other types of cancer
Citation:
Chiara Ambrogio, PhD (2016). Identifying Gene Expression of Early Lung Cancer Exposes More Drug Targets
Last Updated on February 12, 2016 by Marie Benz MD FAAD