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Teaching With Isogenics: In Vitro Testing of the Stratified Medicine Approach used by the National Lung Matrix Trial

Jun 10, 2016 1:56:20 PM No Comments

A number of scientists and clinicians in Glasgow are currently participating in the National Lung Matrix Trial (NLMT), which aims to expand the use of stratified medicine approaches for the treatment of non-small cell lung carcinoma (NSCLC), by testing the efficiency of selected biomarker-targeted therapy combinations.

In the trial, NSCLC patients will be profiled using targeted genomic sequencing and assigned to one of 18 molecular cohorts depending on the presence or absence of specific mutations, and will be treated with drugs that target these particular mutant phenotypes. Successful drug-biomarker combinations will then be followed up in further investigations.

To better help the University's students understand the stratified medicine approaches that are being developed for cancer treatment, Horizon has volunteered the use of its X-MAN® Isogenic Cell Lines to recreate the trial in the lab. This multi-student project will test several of the drugs used in the NLMT on NSCLC, colon cancer and breast cancer cell lines that express biomarkers corresponding to different molecular cohorts, e.g. activated EGFR, activated KRAS.

Prof. Nicol Keith, Director of Research Impact at University of Glasgow said "Using isogenic lines for this project links beautifully into the lecture components on genomics and personalized therapies as well as understanding the basics of key gene changes in cancer, and connects key current concepts in cancer biology and cancer therapy to the practical skills."

The first aim of the project will be to test the hypothesis that cells expressing particular biomarkers will be sensitive to the cognate targeted therapy. This will involve performing survival assays on cultured cells to determine the IC50 for the test and control drugs. Western blotting will be used to determine whether the drugs inhibit the predicted signalling pathways.

It is possible that the presence of other cancer-related mutations in these cell lines will modulate the sensitivity of the cells to these drugs, and the availability of genome-wide sequence data will assist in the interpretation of the results.

The second aim of the project is to investigate whether the development of resistance to one targeted therapy also confers resistance to other drugs. Cells will be cultured under very low concentrations of drug for several weeks with the aim of selecting resistant clones. The resulting cell lines will be tested for resistance to a panel of drugs.

The students at Glasgow will be working with a wide range of cell lines and drugs, and so will be working as a team to get through them all. Each student will test a different combination of biomarker-containing cell lines and targeted therapies, such that the team as a whole will generate a valuable and informative set of data.

And as Glasgow is participating in the NLMT, the students will meet scientists and clinicians involved in collecting pre-treatment patient samples, performing high throughput sequencing, treating the patients, and analysing samples during the trial. This will enable them to see how their work at the bench fits in with translational research, and will help them understand how researchers from different disciplines can work together to make significant advances in patient treatment.

We look forward to catching up with the students in a few months to find out how their projects have gone!

More information: The National Lung Matrix Trial: translating the biology of stratification in advanced non-small-cell lung cancer. Middleton et al (2015) Ann. Oncology, 26(12):2464-9.

Learn more about X-MAN Isogenic Cell Lines

 

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