Résumé
Prostate cancer is one of the leading causes of death from cancer in men and its incidence is constantly rising. In most cases, the prognosis of patients is defined according to staging, PSA levels and Gleason score, which differentiates low grade (Gleason < 4) and high grade (Gleason ≥ 4) cancers. High-grade tumors are associated with high metastatic potential and poor prognosis. They are currently treated with hormone therapy, to which docetaxel is added when they become resistant to the anti-androgen. However, response rates remain very low. Clinical trials with other chemotherapeutic agents such as mitoxantrone, vinorelbine or oxaliplatin have been performed, yet with limited success. It was reported that an expression signature of 86 genes could distinguish low-grade and high-grade tumors, with a reliability of 81% (True et al. PNAS 2006 103:10991-6). We used an in silico approach to explore the NCI databases, which allow access to both gene expression profiles of 60 human tumor cell lines and their in vitro sensitivity to thousands of anticancer drugs. After extraction of the expression profiles of the 86 genes of the True's signature, we calculated, for each gene, the Pearson coefficients of correlation (r) between their expression level in the 60 cell lines and cell sensitivity to 140 core anticancer compounds, expressed as the antilog of IC50. A positive r-value is associated to drug efficacy, whereas a negative r-value is associated to drug resistance. Among the 86 genes, the expression of 45 genes was correlated with the sensitivity to various compounds with an r-value +0.3 (p<0.01). Among them, 18 genes showed a correlation with the sensitivity to platinum compounds, in particular SHMT2 whose expression was positively correlated with the sensitivity to oxaliplatin but not to cisplatin. SHMT2 encodes the mitochondrial isoform of serine hydroxymethyl transferase, which converts glycine to serine, which is then exported to the cytoplasm to generate the one-carbon units that are required for the biosynthesis of purines. Since SHMT2 is overexpressed in high grade prostate cancers, we tested the effect of SHMT2 downregulation on oxaliplatin sensitivity. siRNA-mediated donwregulation of SHMT2 in DU145 or LNCaP prostate tumor cell lines rendered cells resistant to oxaliplatin but not to cisplatin. Conversely, downregulation of SHMT2 in control benign prostatic hyperplasia cells did not induce a significant change in sensitivity to both drugs. Together, our data provide the first functionnal evidences that oxaliplatin could be used as a potential alternative therapy for high-grade prostate cancers overexpressing SHMT2.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2692.