Abstract
Proteomics and bioinformatics are a useful combined technology for the characterization of protein expression level and modulation associated with the response to a drug and with its mechanism of action. The folate pathway represents an important target in the anticancer drugs therapy. In the present study, a discovery proteomics approach was applied to tissue samples collected from ovarian cancer patients who relapsed after the first-line carboplatin-based chemotherapy and were treated with pemetrexed (PMX), a known folate pathway targeting drug. The aim of the work is to identify the proteomic profile that can be associated to the response to the PMX treatment in pre-treatement tissue. Statistical metrics of the experimental Mass Spectrometry (MS) data were combined with a knowledge-based approach that included bioinformatics and a literature review through ProteinQuest™ tool, to design a protein set of reference (PSR). The PSR provides feedback for the consistency of MS proteomic data because it includes known validated proteins. A panel of 24 proteins with levels that were significantly different in pre-treatment samples of patients who responded to the therapy vs. the non-responder ones, was identified. The differences of the identified proteins were explained for the patients with different outcomes and the known PMX targets were further validated. The protein panel herein identified is ready for further validation in retrospective clinical trials using a targeted proteomic approach. This study may have a general relevant impact on biomarker application for cancer patients therapy selection.
Highlights
The folate pathway is an important biochemical target for anti-cancer drugs and overall more than 1,500 clinical trials are currently running (WWW.clinicaltrials.gov); it represents an active wide field of study today (Wilson et al, 2014; Taddia et al, 2015).After first line treatment of ovarian cancer (OC) patients with platinum drugs, drug resistance occurs rapidly inducing the overexpression of folate-dependent proteins such as thymidylate synthase (TS, TYSY) (Ozasa et al, 2010), dihydrofolate reductase (DHFR, DYR), the trifunctional purine biosynthetic protein adenosine-3 (GART, PUR2) and other enzymes involved in cell replication
Identification of a protein subset that characterizes the activity of folate metabolism targeted Ph.D. thesis
In our studies we identified ovarian cancer tissue samples that were collected from patients who received platinum drugs as first line therapy, showed drug resistance and were treated with PMX as second line therapy
Summary
The folate pathway is an important biochemical target for anti-cancer drugs and overall more than 1,500 clinical trials are currently running (WWW.clinicaltrials.gov); it represents an active wide field of study today (Wilson et al, 2014; Taddia et al, 2015). After first line treatment of ovarian cancer (OC) patients with platinum drugs, drug resistance occurs rapidly inducing the overexpression of folate-dependent proteins such as thymidylate synthase (TS, TYSY) (Ozasa et al, 2010), dihydrofolate reductase (DHFR, DYR), the trifunctional purine biosynthetic protein adenosine-3 (GART, PUR2) and other enzymes involved in cell replication. PMX is already in use in colon and pancreatic cancer, as well as in mesothelioma patients sensitive to TS targeting drugs (https:// www.drugbank.ca/), and it was proposed for use in a clinical phase II trial for the treatment of resistant OC (Vergote et al, 2009). The proper selection of the sub-population that could respond to the proposed therapy could improve the outcome, if suitable biomarkers to predict PMX response can be identified
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