| Abstract |
The discovery of oncogenes, tumor suppressors and susceptibility genes
have demonstrated that cancer is related to changes in the genome.
However, the wide variety of molecular alterations observed among inter
and intra tumor types greatly difficults the development of effective
anticancer therapies and appropriate biomarkers for the early selection of
patients. In this work, we describe the establishment of different panels
of cell lines derived from human tumor samples. Due to their low passage
number, these cell lines retained part of the molecular characteristics
found in the original tumor. This system represented a suitable model to
perform pharmacogenomic studies that help to envisage future clinical
responses. Using this cell panel, we carried out comparative studies
between the expression profiles of different genes commonly altered in
cancer and their response to different drugs currently used in clinical
oncology. In addition, using validated bio-informatic tools, we generated
data matrices that helped us to identify putative response biomarkers for
three new marine-derived antitumor drugs -Yondelis, Aplidin and Zalypsis -
developed by the Spanish biopharmaceutical company PharmaMar. On studying
the relationship between the sensitivity of the different cell lines to
Yondelis and the expression of the selected biomarkers, we observed a
highly significant correlation between the presence or absence of p53 and
its sensibility to the drug. Dose-response functional analyses using
isogenic cell lines expressing or not p53, showed that the absence of p53
consistently increased the sensibility to Yondelis. In addition, we
demonstrated that the drug induced the accumulation of p53, although it
was not associated with the transcription of its known target genes Bax or
p21CIP1. On the other hand, we observed a p53 dependent MAPK/ERK kinase
activation. Concerning Aplidin, we observed a significant correlation
between the cells sensibility to the drug and low expression levels of
p27KIP1. Furthermore, cell lines with knocked-down p27KIP1 or null MEFs
were much more sensitive to Aplidin than their respective wild-type
counterparts. Also, we observed that Aplidin increased the cellular
content of p27KIP1 by an oxidation-dependent mechanism, as demonstrated by
the inhibition of the Aplidin-induced increase in p27KIP1 levels by the
addition of antioxidants. Finally, regarding Zalypsis, we found a clear
relationship between the sensibility to the drug and low levels of
PDGFRalpha in both in vitro and in vivo in xenotransplantes models. In
summary, our results suggest p53, p27KIP1 and PDGFRalpha as predictive
response biomarkers for the new antitumor drugs Yondelis, Aplidin and
Zalypsis, respectively.
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