Article

Expression of choline kinase alpha to predict outcome in patients with early-stage non-small-cell lung cancer: a retrospective study.

Translational Oncology Unit, CSIC-UAM-La Paz, National Center of Biotechnology, Madrid, Spain.
The Lancet Oncology (Impact Factor: 24.73). 11/2007; 8(10):889-97. DOI: 10.1016/S1470-2045(07)70279-6
Source: PubMed

ABSTRACT Adequate prognostic markers to predict outcome of patients with lung cancer are still needed. The aim of this study was to assess whether choline kinase alpha (ChoKalpha) gene expression could identify patients with different prognoses. ChoKalpha is an enzyme involved in cell metabolism and proliferation and has a role in oncogene-mediated transformation in several human tumours, including lung cancer.
60 patients with non-small-cell lung cancer (NSCLC) who had undergone surgical resection in a single centre were enrolled into the study as the training group. We used real-time reverse-transcriptase PCR (RT-PCR) to measure ChoKalpha gene expression and analyse the association between ChoKalpha expression and survival in evaluable patients. Additionally, a second group of 120 patients with NSCLC from a different hospital were enrolled into the study as the validation group. We did an overall analysis of all 167 patients who had available tissue to confirm the cut-off point for future studies. The primary endpoints were lung-cancer-specific survival and relapse-free survival.
Seven of the 60 patients in the training group were not evaluable due to insufficient tissue. In the 53 evaluable patients, the cut-off for those with ChoKalpha overexpression was defined by receiver operator under the curve (ROC) methodology. 4-year lung-cancer-specific survival was 54.43% (95% CI 28.24-80.61) for 25 patients with ChoKalpha expression above the ROC-defined cut-off compared with 88.27% (75.79-100) for 28 patients with concentrations of the enzyme below this cut-off (hazard ratio [HR] 3.14 [0.83-11.88], p=0.07). In the validation group, six of the 120 enrolled patients were not evaluable due to insufficient tissue. For the other 114 patients, 4-year lung-cancer-specific survival was 46.66% (32.67-59.65) for those with ChoKalpha expression above the ROC-defined cut-off compared with 67.01% (50.92-81.11) for patients with concentrations of ChoKalpha below the cut-off (HR 1.87 [1.01-3.46], p=0.04). A global analysis of all 167 patients further confirmed the association between ChoKalpha overexpression and worse clinical outcome of patients with NSCLC: 4-year lung-cancer-specific survival for ChoKalpha expression above the ROC-defined cut-off was 49.00% (36.61-60.38) compared with 70.52% (59.80-76.75) for those with concentrations of ChoKalpha below the cut-off (HR 1.98 [1.14-3.45], p=0.01). The overall analysis confirmed the cut-off for ChoKalpha expression should be 1.91-times higher than concentrations noted in healthy tissues when ChoKalpha is used as an independent predictive factor of relapse-free and lung-cancer-specific survival in patients with early-stage NSCLC.
ChoKalpha expression is a new prognostic factor that could be used to help identify patients with early-stage NSCLC who might be at high risk of recurrence, and to identify patients with favourable prognosis who could receive less aggressive treatment options or avoid adjuvant systemic treatment. New treatments that inhibit ChoKalpha expression or activity in patients with lung cancer should be studied further.

Download full-text

Full-text

Available from: Marcin Skrzypski, Jul 28, 2015
0 Followers
 · 
161 Views
  • Source
    • "Recent studies on the biological function of ChoK isozymes revealed that ChoKa may play a more prominent role in cancer development as compared to ChoKb, as only ChoKa was upregulated in breast cancer cell lines [9] and specific depletion of the ChoKa isoform by shRNA selectively induced apoptosis in several tumor-derived cell lines without affecting the viability of normal primary cells [10]. The ChoKa isoform has also been proposed as a new prognostic marker for predicting the clinical outcome in patients with non-small-cell lung cancer [11]. These observations have resulted in the development of an antitumoral strategy focused on ChoK inhibition. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Inhibition of Choline Kinase (ChoK) has been reported as a therapeutical target in the treatment of some kinds of tumor. In this paper, the design and synthesis of new non-symmetrical monocationic ChoK inhibitors is described, bearing a cationic head and an adenine moiety connected by linkers of different lengths. Docking studies indicate that the cationic head of these compounds could be inserted into the choline binding site of the enzyme, while the adenine moiety could be stabilized into the ATP binding site. Docking studies also support the difference of activity of the synthesized compounds, which depends on both the substituent at position 4 of the cationic head and the linker length, being dimethylamine and 1,4-diphenylbutane respectively, the most appropriate ones. Compounds 14 (IC(50) = 10.70 ± 0.40 μM) and 17 (IC(50) = 6.21 ± 0.97 μM) are the most potent ChoK inhibitors and suitable for further modification with a view to obtain more potent antitumor compounds.
    European Journal of Medicinal Chemistry 02/2012; 50:154-62. DOI:10.1016/j.ejmech.2012.01.050 · 3.43 Impact Factor
  • Source
    • "In the past years, it has been found that besides its structural function, the alpha isoform (ChoKα) is closely related to the regulation of cell growth, playing a relevant role in cell transformation and in the carcinogenic process (Lacal, 2001; Nakagami et al., 1999; Ramirez de Molina et al., 2005; Ramirez de Molina et al., 2002a; Ramirez de Molina et al., 2002b). Furthermore, a recent study performed in earlystage non-small cell lung cancer patients, points at ChoKα as a new relevant factor useful to identify patients with poor prognosis that could be susceptible of a different strategy of treatment (Ramirez de Molina et al., 2007). By contrast, recent evidences demonstrate that ChoKβ is not able to induce cell transformation due to a differential behaviour in phospholipids metabolism under in vivo conditions (Gallego-Ortega et al., 2009). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Bladder cancer is one of the most common causes of death in industrialized countries. New tumor markers and therapeutic approaches are still needed to improve the management of bladder cancer patients. Choline kinase-alpha (ChoKalpha) is a metabolic enzyme that has a role in cell proliferation and transformation. Inhibitors of ChoKalpha show antitumoral activity and are expected to be introduced soon in clinical trials. This study aims to assess whether ChoKalpha plays a role in the aggressiveness of bladder tumors and constitutes a new approach for bladder cancer treatment. We show here that ChoKalpha is constitutively altered in human bladder tumor cells. Furthermore, in vivo murine models, including an orthotopic model to mimic as much as possible the physiological conditions, revealed that increased levels of ChoKalpha potentiate both tumor formation (P< or =0.0001) and aggressiveness of the disease on different end points (P=0.011). Accordingly, increased levels of ChoKalpha significantly reduce survival of mice with bladder cancer (P=0.05). Finally, treatment with a ChoKalpha-specific inhibitor resulted in a significant inhibition of tumor growth (P=0.02) and in a relevant increase in survival (P=0.03).
    Oncogene 06/2009; 28(26):2425-35. DOI:10.1038/onc.2009.91 · 8.56 Impact Factor
Show more