Author of

• 11543

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  P2.06 - Poster Session 2 - Prognostic and Predictive Biomarkers (ID 165)

  • Event: WCLC 2013
  • Type: Poster Session
  • Track: Biology
  • Presentations: 1
  • Moderators:
  • Coordinates: 10/29/2013, 09:30 - 16:30, Exhibit Hall, Ground Level

  • 11559

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    P2.06-016 - Expression and clinical significance of the monocarboxylate transporter MCT1 as a novel therapeutic target in Small-Cell-Lung-Cancer (SCLC) (ID 1473)

    09:30 - 09:30  |  Author(s): F. Trapani
    • Abstract

    Background
    Small cell lung is a rapidly proliferating disease. Because of its high proliferation index, cancer cells rely on glycolysis, rather than oxidative phosphorylation, for ATP generation. Furthermore SCLC tumours often contain regions of hypoxia which switches tumour cells to a glycolytic phenotype. Increased glycolysis leads to increased lactate production which is effluxed from the cell in order to prevent reduced intracellular pH or inhibition of metabolic pathways via the monocarboxylate transporter (MCT) proteins MCT1 and MCT4. Inhibition of these transporters has been proposed as a method of selectively targeting highly glycolytic cancer cells. AZD3965 is an orally bioavailable MCT1 specific inhibitor currently under evaluation in phase I clinical trials. In an in vitro model of SCLC we have recently shown that in hypoxic conditions resistance to AZD3965 is associated with increased MCT4 levels (Polanski et al. submitted). Aim: To examined the expression and clinical significance of MCT1 and MCT4 in SCLC.

    Methods
    Archival SCLC biopsy specimens and clinical data from 78 patients presenting to the University Hospital of South Manchester and the Christie Hospital between 1994 and 2005 were analyzed. Nine representative cores from the tumour specimens were used to generate three TMAs. Sections were then stained for the markers MCT1, MCT4 and for the hypoxic marker CAIX. Staining was evaluated by two independent scorers and extent and intensity of the staining were estimated. A combined score for each case was calculated as the mean product of extent and intensity for all the cores in a case. The association between MCT1, MCT4 or CAIX and known prognostic factors was evaluated by Fisher’s exact test. Kaplan-Meier analysis was used to assess overall survival rates and Log Rank test was used for the comparison of the survival distributions.

    Results
    The proportion of tumours with any expression of MCT1, MCT4 or CAIX was 99%, 99%, 90% respectively. Higher levels of expression (intensity x extent) were observed for MCT1 (median=8.17) compared to MCT4 (median=2.21; p<0.001). A positive correlation was observed for CAIX expression and MCT4 expression. Tumours with CAIX expression, high MCT1 expression (>median) and low MCT4 expression ( 10 x 109/L, platelets < 150 x 109/L, Na < 135 mmol/L; LDH > 550 IU/L). However, high MCT1 expression score was associated with worse survival (14 vs. 32 months; p=0.019). Neither MCT4 nor CAIX expression was prognostic. Of the known prognostic factors assessed, extensive stage was significantly associated with shorter overall survival (6 vs. 27 months; p<0.001).

    Conclusion
    MCT1 and MCT4 are often expressed in SCLC and 21% cases in this series express a pattern associated with potential sensitivity to MCT1 inhibition. Higher expression of MCT1 is an adverse prognostic factor in univariate analysis reinforcing further evaluation of MCT1 inhibition in this disease.