Faculty Bibliography

While long-term survival rates for early-stage lung cancer are high, most cases are diagnosed in later stages that can negatively impact survival rates. We aim to design a simple, single biomarker blood test for early-stage lung cancer that is robust to preclinical variables and can be readily implemented in the clinic. Whole blood was collected in PAXgene tubes from a training set of 29 patients, and a validation set of 260 patients, of which samples from 58 patients were prospectively collected in a clinical trial specifically for this study. After RNA was extracted, the expression of FPR1 and a reference gene were quantified by an automated one-step Taqman RT-PCR assay. Elevated levels of FPR1 mRNA in whole blood predicted lung cancer status with a sensitivity of 55% and a specificity of 87% on all validation specimens. The prospectively collected specimens had a significantly higher 68% sensitivity and 89% specificity. Results from patients with benign nodules were similar to healthy volunteers. No meaningful correlation was present between our test results and any clinical characteristic other than lung cancer diagnosis. FPR1 mRNA levels in whole blood can predict the presence of lung cancer. Using this as a reflex test for positive lung cancer screening computed tomography (CT) scans has the potential to increase the positive predictive value. This marker can be easily measured in an automated process utilizing off-the-shelf equipment and reagents. Further work is justified to explain the source of this biomarker.

PURPOSE: To establish a novel panel of cancer-specific methylated genes for cancer detection and prognostic stratification of early stage non-small cell lung cancer (NSCLC). EXPERIMENTAL DESIGN: Identification of differentially methylated regions (DMRs) was performed with bumphunter on "The Cancer Genome Atlas (TCGA)" dataset, and clinical utility was assessed using quantitative methylation-specific PCR assay in multiple sets of primary NSCLC and body fluids that included serum, pleural effusion, and ascites samples. RESULTS: A methylation panel of 6 genes (CDO1, HOXA9, AJAP1, PTGDR, UNCX, and MARCH11) was selected from TCGA dataset. Promoter methylation of the gene panel was detected in 92.2% (83/90) of the training cohort with a specificity of 72.0% (18/25) and in 93.0% (40/43) of an independent cohort of stage IA primary NSCLC. In serum samples from the later 43 stage IA subjects and population-matched 42 control subjects, the gene panel yielded a sensitivity of 72.1% (31/41) and specificity of 71.4% (30/42). Similar diagnostic accuracy was observed in pleural effusion and ascites samples. A prognostic risk category based on the methylation status of CDO1, HOXA9, PTGDR, and AJAP1 refined the risk stratification for outcomes as an independent prognostic factor for an early stage disease. Moreover, the paralogue group for HOXA9, predominantly overexpressed in subjects with HOXA9 methylation, showed poor outcomes. CONCLUSION: Promoter methylation of a panel of 6 genes has potential for use as a biomarker for early cancer detection and to predict prognosis at the time of diagnosis.

PURPOSE: Diagnosis of lung cancer at an earlier stage results in improved survival, and many cancer-related biomarkers have been studied for their potential roles in early lung cancer detection. One underutilized strategy for biomarker development is the use of mixed panels consisting of combinations of different biomarkers that may increase sensitivity and specificity. We examined correlations among previously studied biomarkers with the goal of identifying an ideal panel of biomarkers with an enhanced discriminatory ability for lung cancer. METHODS: Case and smoker control samples were selected from the NYU Lung Cancer Biomarker Center (part of the NCI Early Detection Research Network). The NYU cohort consisted of high risk smokers who participated in low-dose computed tomography (LDCT) lung cancer screening. Serum samples from each individual were used to develop four different bloodbased platform testing 34 biomarkers, over the last 5 years - Luminex technology for matrix metalloproteinase (MMPs); enzymelinked immunosorbent assay (ELISA) for Achaete-scute homolog 1 (ASCL1), forkhead box P3 (FOXP3), and autoantibodies to tumor associated antigens (TAAs); millipore bead-based immunoassay for 13 cytokines. Statistical analyses were performed using Spearman's correlation. RESULTS: 31 of the 1122 biomarker-biomarker correlations were statistically significant. Eighteen of the significant correlations were in cancer patients, including : MDM2-IL4, MDM2-IL6, IL17-IMP1, MMP9-TNFA, MMP7-FOXP3, MMP10-FOXP3, and MMP10-P62. There was a strong positive correlation between MDM2 and IL4 in lung cancer patients (p=0.002). There was also a strong positive correlation between MDM2 and IL6 in cancer patients (p= 0.001). In non-cancer patients, these two correlations were not significant CONCLUSIONS: In this study we found 18 serum biomarker-biomarker correlations which were significant in cancer patients. MDM2-IL4 and MDM2-IL6 were two strong positive correlates which were not seen in non-cancer patients

Despite the immune-reconstitution with antiretroviral therapy (ART), HIV-infected individuals remain highly susceptible to tuberculosis (TB) and have an enrichment of oral anaerobes in the lung. Products of bacterial anaerobic metabolism, like butyrate and other short-chain fatty acids (SCFAs), induce regulatory T cells (Tregs). We tested whether SCFAs contribute to poor TB control in a longitudinal cohort of ART-treated HIV-infected South Africans. Increase in serum SCFAs was associated with increased TB susceptibility. SCFAs inhibited IFN-gamma and IL-17A production in peripheral blood mononuclear cells from HIV-infected ART-treated individuals in response to M. tuberculosis antigen stimulation. Pulmonary SCFAs correlated with increased oral anaerobes, such as Prevotella in the lung, and with M. tuberculosis antigen-induced Tregs. Metabolites from anaerobic bacterial fermentation may, therefore, increase TB susceptibility by suppressing IFN-gamma and IL-17A production during the cellular immune response to M. tuberculosis.

Lung cancer is the leading cause of cancer mortality in the United States with non-small cell lung cancer (NSCLC) adenocarcinoma being the most common histological type. Early perturbations in cellular metabolism are a hallmark of cancer, but the extent of these changes in early stage lung adenocarcinoma remains largely unknown. In the current study, an integrated metabolomics and proteomics approach was utilized to characterize the biochemical and molecular alterations between malignant and matched control tissue from 27 subjects diagnosed with early stage lung adenocarcinoma. Differential analysis identified 71 metabolites and 1102 proteins that delineated tumor from control tissue. Integrated results indicated four major metabolic changes in early stage adenocarcinoma: (1) increased glycosylation and glutaminolysis; (2) elevated Nrf2 activation; (3) increase in nicotinic and nicotinamide salvaging pathways; and (4) elevated polyamine biosynthesis linked to differential regulation of the SAM/nicotinamide methyl-donor pathway. Genomic data from publicly available databases were included to strengthen proteomic findings. Our findings provide insight into the biochemical and molecular biological reprogramming that may accompanies early stage lung tumorigenesis and highlight potential therapeutic targets.