Faculty Bibliography

PURPOSE: Malignant mesothelioma is a devastating disease with a need for new treatment strategies. In the present study, we showed the importance of extracellular signal-regulated kinase 5 (ERK5) in malignant mesothelioma tumor growth and treatment. EXPERIMENTAL DESIGN: ERK5 as a target for malignant mesothelioma therapy was verified using mesothelial and mesothelioma cell lines as well as by xenograft severe combined immunodeficient (SCID) mouse models. RESULTS: We first showed that crocidolite asbestos activated ERK5 in LP9 cells and mesothelioma cell lines exhibit constitutive activation of ERK5. Addition of doxorubicin resulted in further activation of ERK5 in malignant mesothelioma cells. ERK5 silencing increased doxorubicin-induced cell death and doxorubicin retention in malignant mesothelioma cells. In addition, shERK5 malignant mesothelioma lines exhibited both attenuated colony formation on soft agar and invasion of malignant mesothelioma cells in vitro that could be related to modulation of gene expression linked to cell proliferation, apoptosis, migration/invasion, and drug resistance as shown by microarray analysis. Most importantly, injection of shERK5 malignant mesothelioma cell lines into SCID mice showed significant reduction in tumor growth using both subcutaneous and intraperitoneal models. Assessment of selected human cytokine profiles in peritoneal lavage fluid from intraperitoneal shERK5 and control tumor-bearing mice showed that ERK5 was critical in regulation of various proinflammatory (RANTES/CCL5, MCP-1) and angiogenesis-related (interleukin-8, VEGF) cytokines. Finally, use of doxorubicin and cisplatin in combination with ERK5 inhibition showed further reduction in tumor weight and volume in the intraperitoneal model of tumor growth. CONCLUSION: ERK5 inhibition in combination with chemotherapeutic drugs is a beneficial strategy for combination therapy in patients with malignant mesothelioma. Clin Cancer Res; 19(8); 2071-83. (c)2013 AACR.

Objective: Glycomics is an emerging area for understanding carcinogenesis; studies in glycobiology have documented that aberrant glycosylation accompanies malignant transformation. We have used glycomic profiling of serum using nano-liquid chromatography-mass spectrometry and using biostatistics we report glycomics patterns distinguishing between non-small cell lung cancer cases (NSCLC) versus healthy controls. Methods: First, we obtained pre-operative sera of non-small lung cancer cases (Stages I-II) and healthy controls from the NYU biorepository. The serum sample set consisted of 50 lung cancer (adenocarcinoma) patients, 50 healthy controls and 28 COPD patients, matched on gender, smoking status, pack/year for smokers, and as best as possible for age. The samples are analyzed by extracting the N-glycans in sera and measuring the relative concentrations using nano-liquid chromatography-mass spectrometry (nano-LC-MS). Bioinformatic analysis was performed to identify glycans that are differentially present in patients with cancer compared to COPD and healthy controls using feature selection and classification algorithms. We further investigated whether a combination of multiple glycans (i.e. multiplex classifier) could improve predictive performance over individual glycans. Results: Of 330 glycans detected in the NYU serum set, twenty glycans were significantly differentiating (either over- or under-expressed) between cancer, COPD and controls at a false discovery rate < 0.05. Of these glycan features, 11 were different between cancer samples and control samples, while 14 glycans differed significantly between cancer samples and COPD samples. COPD samples differed significantly from Control samples for only one glycan in concentration, indicating large similarity in the glycosylation pattern between COPD and controls. Based on the glycomic profiles, cancer cases were well separated from both control and COPD samples, while COPD and control samples were not discriminated well from each other. Th!

The leading cause of lung cancer is exposure to cigarette smoke and other environmental pollutants, which include formaldehyde, acrolein, benzene, dioxin, and polycyclic aromatic hydrocarbons (PAHs). PAHs and dioxins are exogenous ligands that directly bind to the aryl hydrocarbon receptor (AhR), a transcription factor that activates xenobiotic metabolism, histone modification (an important step in DNA methylation) and, ultimately, tumorigenesis. In this review article we summarize the current understanding of AhR and its role in the development of lung cancer, including its influence on cell proliferation, angiogenesis, inflammation, and apoptosis.

BAP1 is a deubiquitylase that is found associated with multiprotein complexes that regulate key cellular pathways, including the cell cycle, cellular differentiation, cell death, gluconeogenesis and the DNA damage response (DDR). Recent findings indicate that germline BAP1 mutations cause a novel cancer syndrome that is characterized, at least in the affected families that have been studied so far, by the onset at an early age of benign melanocytic skin tumours with mutated BAP1, and later in life by a high incidence of mesothelioma, uveal melanoma, cutaneous melanoma and possibly additional cancers.