Glutaminase enzyme (GLS1) in small cell lung cancer Open Access

Owonikoko, Taofeek K (2014)

Permanent URL: https://etd.library.emory.edu/concern/etds/3r074v241?locale=en
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Abstract

Small cell lung cancer (SCLC) is a fatal disease with limited treatment options. A better understanding of the biology of this disease is needed to guide new treatment options that will result in improved outcomes. Glutaminase enzyme (GLS1) catalyzes the conversion of glutamine to glutamic acid. Preclinical work suggests that this enzyme impacts efficacy of chemotherapeutics used for the treatment of SCLC. The current work was therefore conducted to characterize the expression of GLS1 in SCLC and to assess the association between expression and survival in these patients. The study employed tissues samples of patients diagnosed and treated for SCLC at Emory University. Archival surgical resection samples were employed to determine expression using a standard immunohistochemistry approach. Clinical characteristics and patient outcomes, overall survival (OS) and progression free survival (PFS), were obtained by review of the electronic medical record and summarized using descriptive statistics. Differences in GLS1 expression across race, gender and ethnicity were assessed using t-test, chi-square test or Kruskal-Wallis test based on the distribution of the data. Differences in survival between patient groups defined by GLS1 expression level were tested using Log-rank test and potential covariates were adjusted with Cox proportional hazards model. Statistical significance was set at 0.1 for all analyses. Among the 48 patients for which tissue sample and clinical data was available, median age was 60 years, 58% were females and the majority (79%) were Caucasians. GLS1 expression was significantly higher in normal lung (p= 0.054 ) compared to cancer cells but did not vary significantly by age, gender or race. There was no significant correlation between GLS1 and its other isoform, GLS2, or with the counteracting enzyme, glutamine synthetase (GS). GLS1 expression impacted both progression free survival (PFS) and overall survival (OS) in an age-dependent manner. In conclusion, this study successfully characterized the expression pattern of GLS1 and showed a higher expression in normal lung tissue in comparison to SCLC. It also showed that high GLS1 expression associates significantly with better OS and PFS.

Table of Contents

INTRODUCTION BACKGROUND METHODS Figure 1: Causal Diagram Figure 2: Staining intensity scoring algorithm Figure 3: Immunoscore determination RESULTS Figure 4: Consort diagram DISCUSSION/CONCLUSIONS REFERENCES TABLES / FIGURES Table 1 - Patient Distribution by Demographics and Treatment (n=48) Table 2 - Expression of GLS1, GLS2 and GS by patient demographics and treatment Table 3 - Correlation between Glutaminase (GLS1) and other associated proteins (GLS2 and GS) However, since the probability that the observed correlation between GLS2 and GS could have been due to chance given that the null hypothesis is true is 0.002, which is less than 0.1, we have sufficient evidence to reject the null hypothesis that the correlation between GLS2 and GS is 0.Table 4 - Multivariable analysis of GLS1 expression and OS Table 5 - Multivariable analysis of GLS1 expression and OS without interaction terms in the model Figure 5 - Normality assumptions for age and GLS1 distribution Figure 6 - Comparison of GLS1 expression in normal lung and SCLC showing a higher median GLS1 expression in normal lung versus SCLC Figure 7: Log-log plot Figure 8 - Univariate analysis of GLS1 expression on PFS Figure 9 - Univariate analysis of GLS1 expression (Dichotomized based on median immunoscore) on OS APPENDIX OF TABLES AND FIGURES: Table A1A - Multivariable analysis of progression free survival by GLS1 expression (measured as intensity of 2+/3+ vs. 0/1+) adjusted for known prognostic factors (age and gender), race, other treatment, and interaction terms between expression and age, gender, race, and any initial treatment in SCLC Table A1B - Multivariable analysis of progression free survival by GLS1 expression (measured as intensity of 0/1+/2+ vs. 3+) adjusted for known prognostic factors (age and gender), race, other treatment, and interaction terms between expression and age, gender, race, and any initial treatment in SCLC Table A1C - Multivariable analysis of progression free survival by GLS1 expression (measured as intensity of 3+ or 2+ vs. 1+) adjusted for known prognostic factors (age and gender), race, other treatment, and interaction terms between expression and age, gender, race, and any initial treatment in SCLC Table A2A - Multivariable analysis of overall survival by GLS1 expression (measured as intensity of 2+/3+ vs. 0/1+) adjusted for demographics, treatment, and interaction terms Table A2B - Multivariable analysis of overall survival by GLS1 expression (measured as intensity of 0/1+/2+ vs. 3+) adjusted for demographics, treatment, and interaction terms Table A2C - Multivariable analysis of overall survival by GLS1 expression (measured as intensity of 3+ or 2+ vs. 1+) adjusted for demographics, treatment, , and interaction terms Table A3A - Multivariable analysis of progression free survival by GLS1 expression immunoscore (treated as a dichotomous variable) adjusted for demographics, treatment, percentage cell staining and interaction terms Table A3B - Multivariable analysis of progression free survival by GLS1 expression immunoscore (treated as a continuous variable) adjusted for demographics, treatment, percentage cell staining and interaction terms Table A4A - Multivariable analysis of OS by GLS1 expression immunoscore (treated as a dichotomous variable) adjusted for demographics, treatment, percentage cell staining and interaction terms Table A4B - Multivariable analysis of OS by GLS1 expression immunoscore (treated as a continuous variable) adjusted for demographics, treatment, percentage cell staining and interaction terms Figure A1A - Kaplan-Meier Curves for GLS1 (0/1+ vs. 2+/3+) on PFS Figure A1B - Kaplan-Meier Curves for GLS1 (0/1+/2+ vs. 3+) on PFS Figure A1C - Kaplan-Meier Curves for GLS1 (1+ vs. 2+ vs. 3+) on PFS Figure A2A - Kaplan-Meier Curves for GLS1 (0/1+ vs. 2+/3+) on OS Figure A2B - Kaplan-Meier Curves for GLS1 (0/1+/2+ vs. 3+) on OS

Figure A2C - Kaplan-Meier Curves for GLS1 (1+ vs. 2+ vs. 3+) on OS

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