Abstract
Treatment of cancer often involves the use of chemotherapeutic agents that
preferentially target tumor cells. The idea behind personalized medicine is to
characterize differences between individual cancer cases that will and to direct the
therapy to those most likely to respond. This will require the identification of reliable
predictive biomarkers for each drug. Currently, we are developing a framework for
systematic biomarker discovery by using a combination of gene expression and CGH
arrays to keep track of consistent changes that take place during resistance acquisition
in cell lines towards two anti-cancer drugs: doxorubicin and paclitaxel. By monitoring
changes at two different levels (DNA and RNA) of the genome and developing multiple
cell lines developing resistance against the same drug under identical conditions, we
were able to separate relevant changes from spurious ones and thus reducing the noise
of the experimental system. Doxorubicin is an anthracycline that exerts its anticancer
effect through intercalation into DNA and inhibition of topoisomerase II, whereas
paclitaxel stabilizes microtubules and disrupts the mitotic spindle. We use expression
and copy number data from two cell lines, MDA-231 and MCF-7, that were grown in
the presence of doxorubicin (n=16) or paclitaxel (n=11), vehicle control (n=2). We
have observed a distinct pattern of chemotherapy-induced genomic changes.
Doxorubicin-induced changes involve greater genomic rearrangements than paclitaxel,
which is with accordance to their mode of action. Our findings are validated on already
existing gene expression profiles of patient cohorts treated with the drugs in question,
and the most promising ones will be chosen for functional validation by RNAi knock
down. Successful validation will improve understanding of drug resistance
mechanisms, suggest future drug targets, and enable more efficacious treatment of
cancer patients.
Original language | English |
---|---|
Journal | Annals of Oncology |
Volume | 22 |
Issue number | 2 |
Pages (from-to) | ii44-ii47 |
ISSN | 0923-7534 |
DOIs | |
Publication status | Published - 2011 |
Event | Conference on Improving Care and Knowledge through Translational Research : Breast Cancer Conference - Brussels, Belgium Duration: 1 Jan 2011 → … Conference number: 3 |
Conference
Conference | Conference on Improving Care and Knowledge through Translational Research : Breast Cancer Conference |
---|---|
Number | 3 |
City | Brussels, Belgium |
Period | 01/01/2011 → … |