Ignacio I Wistuba

Publications (177)1078.52 Total impact

• Article: ETS2 mediated tumor suppressive function and MET oncogene inhibition in human non-small cell lung cancer.

  Mohamed Kabbout, Melinda Garcia, Junya Fujimoto, Diane Liu, Denise Woods, Chi-Wan Chow, Gabriela Mendoza, Amin A Momin, Brian P James, Luisa M Solis Soto, Carmen Behrens, J Jack Lee, Ignacio I Wistuba, Humam Kadara
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  ABSTRACT: PURPOSE: The ETS2 transcription factor is an evolutionarily conserved gene that is deregulated in cancer. We analyzed the transcriptome of lung adenocarcinomas and normal lung tissue by expression profiling and found that ETS2 was significantly down-regulated in adenocarcinomas. In this study, we probed the yet unknown functional role of ETS2 in lung cancer pathogenesis. EXPERIMENTAL DESIGN: Lung adenocarcinomas (n=80) and normal lung tissues (n=30) were profiled using the Affymetrix Human Gene 1.0 ST platform. Immunohistochemical (IHC) analysis was performed to determine ETS2 protein expression in NSCLC histological tissue specimens (n=201). Patient clinical outcome, based on ETS2 IHC expression, was statistically assessed using the log-rank and Kaplan-Meier tests. RNA interference and over-expression strategies were employed to assess effects of ETS2 expression on the transcriptome and on various malignant phenotypes. RESULTS: ETS2 expression was significantly reduced in lung adenocarcinomas compared to normal lung (p<0.001). Low ETS2 IHC expression was a significant predictor of shorter time to recurrence in NSCLC (p=0.009, HR=1.89) and adenocarcinoma (p=0.03, HR=1.86). Moreover, ETS2 was found to significantly inhibit lung cancer cell growth, migration and invasion (p<0.05), and microarray and pathways analysis revealed significant (p<0.001) activation of the HGF pathway following ETS2 knockdown. In addition, ETS2 was found to suppress MET phosphorylation and knockdown of MET expression significantly attenuated (p<0.05) cell invasion mediated by ETS2-specific siRNA. Furthermore, knockdown of ETS2 augmented HGF-induced MET phosphorylation, cell migration and invasion. CONCLUSIONS: Our findings point to a tumor suppressor role for ETS2 in human NSCLC pathogenesis through inhibition of the MET proto-oncogene.
  Clinical Cancer Research 05/2013; · 7.74 Impact Factor
• Article: NeuroD1 regulates survival and migration of neuroendocrine lung carcinomas via signaling molecules TrkB and NCAM.

  Jihan K Osborne, Jill E Larsen, Misty D Shields, Joshua X Gonzales, David S Shames, Mitsuo Sato, Ashwinikumar Kulkarni, Ignacio I Wistuba, Luc Girard, John D Minna, Melanie H Cobb
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  ABSTRACT: Small-cell lung cancer and other aggressive neuroendocrine cancers are often associated with early dissemination and frequent metastases. We demonstrate that neurogenic differentiation 1 (NeuroD1) is a regulatory hub securing cross talk among survival and migratory-inducing signaling pathways in neuroendocrine lung carcinomas. We find that NeuroD1 promotes tumor cell survival and metastasis in aggressive neuroendocrine lung tumors through regulation of the receptor tyrosine kinase tropomyosin-related kinase B (TrkB). Like TrkB, the prometastatic signaling molecule neural cell adhesion molecule (NCAM) is a downstream target of NeuroD1, whose impaired expression mirrors loss of NeuroD1. TrkB and NCAM may be therapeutic targets for aggressive neuroendocrine cancers that express NeuroD1.
  Proceedings of the National Academy of Sciences 04/2013; · 9.68 Impact Factor
• Article: Perfecting the fine-needle aspirate cell block.

  Neda Kalhor, Ignacio I Wistuba
  Cancer Cytopathology 03/2013; 121(3):109-10. · 3.33 Impact Factor
• Article: Human lung epithelial cells progressed to malignancy through specific oncogenic manipulations.

  Mitsuo Sato, Jill E Larsen, Woochang Lee, Han Sun, David S Shames, Maithili P Dalvi, Ruben D Ramirez, Hao Tang, J Michael Dimaio, Boning Gao, Yang Xie, Ignacio I Wistuba, Adi F Gazdar, Jerry W Shay, John D Minna
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  ABSTRACT: We used CDK4/hTERT-immortalized normal human bronchial epithelial cells (HBECs) from several individuals to study lung cancer pathogenesis by introducing combinations of common lung cancer oncogenic changes (p53, KRAS, MYC) and followed the stepwise transformation of HBECs to full malignancy. This model demonstrated that: 1) the combination of five genetic alterations (CDK4, hTERT, sh-p53, KRASV12, and c-MYC) is sufficient for full tumorigenic conversion of HBECs; 2) genetically-identical clones of transformed HBECs exhibit pronounced differences in tumor growth, histology, and differentiation; 3) HBECs from different individuals vary in their sensitivity to transformation by these oncogenic manipulations; 4) high levels of KRASV12 are required for full malignant transformation of HBECs, however prior loss of p53 function is required to prevent oncogene-induced senescence; 5) over-expression of c-MYC greatly enhances malignancy but only in the context of sh-p53+KRASV12; 6) growth of parental HBECs in serum-containing medium induces differentiation while growth of oncogenically manipulated HBECs in serum increases in vivo tumorigenicity, decreases tumor latency, produces more undifferentiated tumors, and induces epithelial-to-mesenchymal transition (EMT); 7) oncogenic transformation of HBECs leads to increased sensitivity to standard chemotherapy doublets; 8) an mRNA signature derived by comparing tumorigenic vs. non-tumorigenic clones was predictive of outcome in lung cancer patients. Collectively, our findings demonstrate this HBEC model system can be used to study the effect of oncogenic mutations, their expression levels, and serum-derived environmental effects in malignant transformation, while also providing clinically translatable applications such as development of prognostic signatures and drug response phenotypes.
  Molecular Cancer Research 02/2013; · 4.29 Impact Factor
• Article: Feasibility of Image-Guided Transthoracic Core-Needle Biopsy in the BATTLE Lung Trial.

  Alda L Tam, Edward S Kim, J Jack Lee, Joe E Ensor, Marshall E Hicks, Ximing Tang, George R Blumenschein, Christine M Alden, Jeremy J Erasmus, Anne Tsao, Scott M Lippman, Waun K Hong, Ignacio I Wistuba, Sanjay Gupta
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  ABSTRACT: BACKGROUND:: As therapy for non-small-cell lung cancer (NSCLC) patients becomes more personalized, additional tissue in the form of core-needle biopsies (CNBs) for biomarker analysis is increasingly required for determining appropriate treatment and for enrollment into clinical trials. We report our experience with small-caliber percutaneous transthoracic (PT) CNBs for the evaluation of multiple molecular biomarkers in BATTLE (biomarker-integrated approaches of targeted therapy for lung cancer elimination), a personalized, targeted therapy NSCLC clinical trial. METHODS:: The medical records of patients who underwent PTCNB for consideration of enrollment in BATTLE were reviewed for diagnostic yield of 11 predetermined molecular markers and procedural complications. Univariate and multivariate analyses of factors related to patient and lesion characteristics were performed to determine possible influences on diagnostic yield. RESULTS:: One hundred and seventy PTCNBs were performed using 20-gauge biopsy needles in 151 NSCLC patients screened for the trial. The biopsy specimens of 82.9% of the patients were found to have adequate tumor tissue for analysis of the required biomarkers. On multivariate analysis, metastatic lesions were 5.4 times more likely to yield diagnostic tissue as compared with primary tumors (p = 0.0079). Pneumothorax and chest tube insertion rates were 15.3% and 9.4%, respectively. CONCLUSIONS:: Image-guided 20-gauge PTCNB is safe and provides adequate tissue for analysis of multiple biomarkers in the majority of patients being considered for enrollment into a personalized, targeted therapy NSCLC clinical trial. Metastatic lesions are more likely to yield diagnostic tissue as compared with primary tumors.
  Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 02/2013; · 4.55 Impact Factor
• Article: Uncommon Epidermal Growth Factor Receptor mutations in non-small cell lung cancer and their mechanisms of EGFR tyrosine kinase inhibitors sensitivity and resistance.

  Erminia Massarelli, Faye M Johnson, Heidi S Erickson, Ignacio I Wistuba, Vassiliki Papadimitrakopoulou
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  ABSTRACT: Therapy targeted against the epidermal growth factor receptor (EGFR) has demonstrated dramatic tumor responses and favorable clinical outcomes in a select group of non-small cell lung cancer (NSCLC) patients whose tumors harbor EGFR activating mutations. The best characterized of the mutations conferring sensitivity to EGFR tyrosine kinase inhibitors (TKIs) are deletions in exon 19 and a point mutation in exon 21 (L858R). Likewise, the most common mutation that confers resistance is the T790M point mutation. However several other mutations have been reported and several have been characterized as regards their role in sensitivity or resistance to EGFR TKIs. Resistance to the EGFR TKIs erlotinib and gefitinib, and the newer irreversible EGFR TKIs is a problem of fundamental importance. Recognition of the presence and significance of specific EGFR mutations is important for appropriate therapeutic implementation of EGFR TKIs and research and development of mutation-specific inhibitors. We summarize the literature and present an overview of the subject of less common EGFR mutations and their clinical significance, with an emphasis on EGFR TKI sensitivity or resistance.
  Lung cancer (Amsterdam, Netherlands) 02/2013; · 3.14 Impact Factor
• Article: Prognostic Significance of Combinations of RNA-Dependent Protein Kinase and EphA2 Biomarkers for NSCLC.

  Chengcheng Guo, Ruping Shao, Arlene M Correa, Carmen Behrens, Faye M Johnson, Maria G Raso, Ludmila Prudkin, Luisa M Solis, Maria I Nunez, Bingliang Fang, Jack A Roth, Ignacio I Wistuba, Stephen G Swisher, Tongyu Lin, Apar Pataer
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  ABSTRACT: INTRODUCTION:: RNA-dependent protein kinase (PKR) is an independent prognostic variable in patients with non-small-cell lung cancer (NSCLC). In the current study, we investigated the correlation between PKR and 25 other biomarkers for NSCLC, identified the markers that could further improve the prognostic significance of PKR and elucidated the mechanisms of interaction between these markers and PKR. METHODS:: Tissue microarray samples obtained from 218 patients with lung cancer were stained with an anti-PKR antibody and antibodies against 25 biomarkers. Immunohistochemical expression was scored and used for Kaplan-Meier survival analysis. The interaction between PKR and EphA2 in NSCLC cell lines was examined. RESULTS:: We found that PKR was associated with EphA2 and that the prognostic information regarding NSCLC provided by the combination of PKR and EphA2 (P/E) was significantly more accurate than that provided by either marker alone. The 5-year overall survival rate in patients with PKR/EphA2 (20%) was significantly lower than that of patients with PKR/EphA2 (74%), patients with PKR/EphA2 (55%) , and patients with PKR/EphA2 (55%) (p < 0.0001). We also found that the PKR:EphA2 (P/E) ratio was significantly associated with prognosis (p < 0.0001). Univariate and multivariate Cox analyses revealed that this P/E combination or ratio was an independent predictor of overall survival. In addition, induction of PKR expression reduced EphA2 protein expression levels in NSCLC cell lines. CONCLUSIONS:: PKR/EphA2 is a significant predictor of prognosis for NSCLC. PKR/EphA2 may be a promising approach to improving screening efficiency and predicting prognosis in patients with NSCLC.
  Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 01/2013; · 4.55 Impact Factor
• Article: A 12-Gene Set Predicts Survival Benefits from Adjuvant Chemotherapy in Non-Small-Cell Lung Cancer Patients.

  Hao Tang, Guanghua Xiao, Carmen Behrens, Joan Schiller, Jeffrey Allen, Chi-Wan Chow, Milind Suraokar, Alejandro Corvalan, Jian-Hua Mao, Michael White, Ignacio I Wistuba, John D Minna, Yang Xie
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  ABSTRACT: PURPOSE: Prospectively identifying who will benefit from adjuvant chemotherapy (ACT) would improve clinical decisions for non-small-cell lung cancer (NSCLC) patients. In this study, we aim to develop and validate a functional gene set that predicts the clinical benefits of ACT in NSCLC. EXPERIMENTAL DESIGN: An 18-hub-gene prognosis signature was developed through a systems biology approach, and its prognostic value was evaluated in six independent cohorts. The 18-hub-gene set was then integrated with genome-wide functional (RNAi) data and genetic aberration data to derive a 12-gene predictive signature for ACT benefits in NSCLC. RESULTS: Using a cohort of 442 Stage I-III NSCLC patients who underwent surgical resection, we identified an 18-hub-gene set which robustly predicted the prognosis of patients with adenocarcinoma in all validation datasets across four microarray platforms. The hub genes, identified through a purely data-driven approach, have significant biological implications in tumor pathogenesis, including NKX2-1, Aurora Kinase A, PRC1, CDKN3, MBIP, RRM2. The 12-gene predictive signature was successfully validated in two independent datasets (N=90 and N=176). The predicted benefit group showed significant improvement in survival after ACT (UT Lung SPORE data: hazard ratio=0.34, p=0.017; JBR.10 clinical trial data: hazard ratio=0.36, p=0.038), while the predicted non-benefit group showed no survival benefit for two datasets (hazard ratio=0.80, p=0.70; hazard ratio= 0.91, p=0.82). CONCLUSIONS: This is the first study to integrate genetic aberration, genome-wide RNAi data, and mRNA expression data to identify a functional gene set that predicts which resectable patients with non-small-cell lung cancer will have a survival benefit with ACT.
  Clinical Cancer Research 01/2013; · 7.74 Impact Factor
• Article: Computed Tomography RECIST Assessment of Histopathologic Response and Prediction of Survival in Patients with Resectable Non-Small-Cell Lung Cancer after Neoadjuvant Chemotherapy.

  William N William, Apar Pataer, Neda Kalhor, Arlene M Correa, David C Rice, Ignacio I Wistuba, John Heymach, J Jack Lee, Edward S Kim, Reginald Munden, Kathryn A Gold, Vassiliki Papadimitrakopoulou, Stephen G Swisher, Jeremy J Erasmus
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  ABSTRACT: INTRODUCTION:: This study's objectives were to determine whether tumor response measured by computed tomography (CT) and evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) correlated with overall survival (OS) in patients with non-small-cell lung cancer (NSCLC) after neoadjuvant chemotherapy and surgical resection. METHODS:: We measured primary tumor size on CT before and after neoadjuvant chemotherapy in 160 NSCLC patients who underwent surgical resection. The relationship between CT-measured response (RECIST) and histopathologic response (≤ 10% viable tumor) and OS were assessed by Kaplan-Meier survival, univariable, and multivariable Cox proportional hazards regression. RESULTS:: There was a statistically significant association between CT-measured response (RECIST) and OS (p = 0.03). However, histopathologic response was a stronger predictor of OS (p = 0.002), with a more pronounced separation of the survival curves when compared with CT-measured response. In multivariable Cox regression analysis, only pathologic stage and histopathologic response were significant predictors of OS. A 41% overall discordance rate was noted between CT RECIST response and histopathologic response. CT RECIST classified as nonresponders a subset of patients with histopathologic response (8 out of 30 points, 27%) who demonstrated prolonged survival after neoadjuvant chemotherapy. CONCLUSION:: We were unable to show that CT RECIST is a reliable predictor of OS in patients with NSCLC undergoing surgical resection after neoadjuvant chemotherapy. The failure of CT RECIST to predict long-term outcome may be because of the inability of CT imaging to consistently identify patients with histopathologic response. CT RECIST may have only a limited role as an efficacy endpoint after neoadjuvant chemotherapy in patients with resectable NSCLC.
  Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 01/2013; · 4.55 Impact Factor
• Article: Three-Dimensional mRNA Measurements Reveal Minimal Regional Heterogeneity in Esophageal Squamous Cell Carcinoma.

  Wusheng Yan, Joanna Shih, Jaime Rodriguez-Canales, Michael A Tangrea, Audrey Player, Lixia Diao, Nan Hu, Alisa M Goldstein, Jing Wang, Philip R Taylor, Scott M Lippman, Ignacio I Wistuba, Michael R Emmert-Buck, Heidi S Erickson
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  ABSTRACT: The classic tumor clonal evolution theory postulates that cancers change over time to produce unique molecular subclones within a parent neoplasm, presumably including regional differences in gene expression. More recently, however, this notion has been challenged by studies showing that tumors maintain a relatively stable transcript profile. To examine these competing hypotheses, we microdissected discrete subregions containing approximately 3000 to 8000 cells (500 to 1500 μm in diameter) from ex vivo esophageal squamous cell carcinoma (ESCC) specimens and analyzed transcriptomes throughout three-dimensional tumor space. Overall mRNA profiles were highly similar in all 59 intratumor comparisons, in distinct contrast to the markedly different global expression patterns observed in other dissected cell populations. For example, normal esophageal basal cells contained 1918 and 624 differentially expressed genes at a greater than twofold level (95% confidence level of <5% false positives), compared with normal differentiated esophageal cells and ESCC, respectively. In contrast, intratumor regions had only zero to four gene changes at a greater than twofold level, with most tumor comparisons showing none. The present data indicate that, when analyzed using a standard array-based method at this level of histological resolution, ESCC contains little regional mRNA heterogeneity.
  American Journal Of Pathology 12/2012; · 4.89 Impact Factor
• Article: g-Protein Coupled Receptor Family C, Group 5, Member A (gprc5a) Expression Is Decreased in the Adjacent Field and Normal Bronchial Epithelia of Patients with Chronic Obstructive Pulmonary Disease and Non-Small-Cell Lung Cancer.

  Junya Fujimoto, Humam Kadara, Melinda M Garcia, Mohamed Kabbout, Carmen Behrens, Diane D Liu, J Jack Lee, Luisa M Solis, Edward S Kim, Neda Kalhor, Cesar Moran, Amir Sharafkhaneh, Reuben Lotan, Ignacio I Wistuba
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  ABSTRACT: : Understanding oncogenes and tumor suppressor genes expression patterns is essential for characterizing lung cancer pathogenesis. We have previously demonstrated that mGprc5a/hGPRC5A is a lung-specific tumor suppressor evidenced by inflammation-mediated tumorigenesis in Gprc5a-knockout mice. The implication of GPRC5A in human lung cancer pathogenesis, including that associated with inflammatory chronic obstructive pulmonary disease (COPD), a risk factor for the malignancy, remains elusive. : We sought to examine GPRC5A immunohistochemical expression in histologically normal bronchial epithelia (NBE) from lung disease-free never- and ever-smokers (n = 13 and n = 18, respectively), from COPD patients with (n = 26) and without cancer (n = 24) and in non-small cell lung cancers (NSCLCs) (n = 474). Quantitative assessment of GPRC5A transcript expression in airways (n = 6), adjacent NBEs (n = 29) and corresponding tumors (n = 6) from 6 NSCLC patients was also performed. : GPRC5A immunohistochemical expression was significantly lower in tumors compared to uninvolved NBE (p < 0.0001) and was positively associated with adenocarcinoma histology (p < 0.001). GPRC5A airway expression was highest in lung disease-free NBE, decreased and intermediate in NBE of cancer-free COPD patients (p = 0.004) and further attenuated and lowest in epithelia of COPD patients with adenocarcinoma and SCC (p < 0.0001). Furthermore, GPRC5A mRNA was significantly decreased in NSCLCs and corre sponding NBE compared to uninvolved normal lung (p = 0.03). : Our findings highlight decreased GPRC5A expression in the field cancerization of NSCLC, including that associated with lung inflammation. Assessment of the use of GPRC5A expression as a risk factor for NSCLC development in COPD patients is warranted.
  Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 12/2012; 7(12):1747-54. · 4.55 Impact Factor
• Article: CXCR2 expression in tumor cells is a poor prognostic factor and promotes invasion and metastasis in lung adenocarcinoma.

  Pierre Saintigny, Erminia Massarelli, Steven Lin, Young-Ho Ahn, Yulong Chen, Sangeeta Goswami, Baruch Erez, Michael S O'Reilly, Diane Liu, J Jack Lee, [......], Carmen Behrens, Luisa M Solis Soto, John V Heymatch, Edward S Kim, Roy S Herbst, Scott M Lippman, Ignacio I Wistuba, Waun Ki Hong, Jonathan M Kurie, Ja Seok Koo
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  ABSTRACT: CXCR2 in non-small cell lung cancer (NSCLC) has been studied mainly in stromal cells and is known to increase tumor inflammation and angiogenesis. Here, we examined the prognostic importance of CXCR2 in NSCLC and the role of CXCR2 and its ligands in lung cancer cells. The effect of CXCR2 expression on tumor cells was studied using stable knockdown clones derived from a murine KRAS/p53-mutant lung adenocarcinoma cell line with high metastatic potential and an orthotopic syngeneic mouse model and in vitro using a CXCR2 small molecule antagonist (SB225002). CXCR2 protein expression was analyzed in tumor cells from 262 NSCLC. Gene expression profiles for CXCR2 and its ligands (CXCR2 axis) were analyzed in 52 human NSCLC cell lines and 442 human lung adenocarcinomas. Methylation of CXCR2 axis promoters was determined in 70 human NSCLC cell lines. Invasion and metastasis were decreased in CXCR2 knockdown clones in vitro and in vivo. SB225002 decreased invasion in vitro. In lung adenocarcinomas, CXCR2 expression in tumor cells was associated with smoking and poor prognosis. CXCR2 axis gene expression profiles in human NSCLC cell lines and lung adenocarcinomas defined a cluster driven by CXCL5 and associated with smoking, poor prognosis and RAS pathway activation. Expression of CXCL5 was regulated by promoter methylation. The CXCR2 axis may be an important target in smoking-related lung adenocarcinoma.
  Cancer Research 11/2012; · 7.86 Impact Factor
• Article: An epithelial-mesenchymal transition (EMT) gene signature predicts resistance to EGFR and PI3K inhibitors and identifies Axl as a therapeutic target for overcoming EGFR inhibitor resistance.

  Lauren Averett Byers, Lixia Diao, Jing Wang, Pierre Saintigny, Luc Girard, Michael Peyton, Li Shen, You-Hong Fan, Uma Giri, Praveen Tumula, [......], J Jack Lee, Scott M Lippman, Kie-Kian Ang, Gordon B Mills, Waun Ki Hong, John N Weinstein, Ignacio I Wistuba, Kevin Coombes, John D Minna, John V Heymach
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  ABSTRACT: PURPOSE: EMT has been associated with metastatic spread and EGFR inhibitor resistance. We developed and validated a robust 76-gene EMT signature using gene expression profiles from four platforms using NSCLC cell lines and patients treated in the BATTLE study. Methods: We conducted an integrated gene expression, proteomic, and drug response analysis using cell lines and tumors from NSCLC patients. A 76-gene EMT signature was developed and validated using gene expression profiles from four microarray platforms of NSCLC cell lines and patients treated in the BATTLE (Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination) study, and potential therapeutic targets associated with EMT were identified. RESULTS: Compared with epithelial cells, mesenchymal cells demonstrated significantly greater resistance to EGFR and PI3K/Akt pathway inhibitors, independent of EGFR mutation status, but more sensitivity to certain chemotherapies. Mesenchymal cells also expressed increased levels of the receptor tyrosine kinase Axl and showed a trend towards greater sensitivity to the Axl inhibitor SGI-7079. Furthermore, the combination of SGI-7079 with erlotinib reversed erlotinib resistance in mesenchymal lines expressing Axl and in a xenograft model of mesenchymal NSCLC. In NSCLC patients, the EMT signature predicted 8-week disease control in patients receiving erlotinib, but not other therapies. CONCLUSION: We have developed a robust EMT signature that predicts resistance to EGFR and PI3K/Akt inhibitors, highlights different patterns of drug responsiveness for epithelial and mesenchymal cells, and identifies Axl as a potential therapeutic target for overcoming EGFR inhibitor resistance associated with the mesenchymal phenotype.
  Clinical Cancer Research 10/2012; · 7.74 Impact Factor
• Article: Characterizing the molecular spatial and temporal field of injury in early stage smoker non-small cell lung cancer patients after definitive surgery by expression profiling.

  Humam Kadara, Li Shen, Junya Fujimoto, Pierre Saintigny, Chi-Wan Chow, Wenhua Lang, Zuming Chu, Melinda Garcia, Mohamed Kabbout, You-Hong Fan, Carmen Behrens, Diane Liu, Li Mao, J Jack Lee, Kathryn A Gold, Jing Wang, Kevin Coombes, Edward S Kim, Waun Ki Hong, Ignacio I Wistuba
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  ABSTRACT: Gene expression alterations in response to cigarette smoke have been characterized in normal-appearing bronchial epithelium of healthy smokers and it has been suggested that adjacent histologically normal tissue display tumor-associated molecular abnormalities. We sought to delineate the spatial and temporal molecular lung field of injury in smoker early stage non-small cell lung cancer (NSCLC) patients (n=19) who were accrued into a surveillance clinical trial for annual follow-up and bronchoscopies within one year after definitive surgery. Bronchial brushings and biopsies were obtained from six different sites in the lung at the time of inclusion in the study and at 12, 24 and 36 months after the first time point. Affymetrix Human Gene 1.0 ST arrays were used for whole-transcript expression profiling of airways (n=391). Microarray analysis identified gene features (n=1165) that were non-uniform by site and differentially expressed between airways adjacent to tumors relative to more distant samples as well as those (n=1395) that were significantly altered with time up to three years. In addition, gene-interaction networks mediated by PI3K and ERK1/2 were modulated in adjacent compared to contralateral airways and the latter network with time. Furthermore, phosphorylated AKT and ERK1/2 immunohistochemical expression were significantly increased with time (nuclear pAKT, p=0.03; cytoplasmic pAKT, p<0.0001; pERK1/2, p=0.02) and elevated in adjacent compared to more distant airways (nuclear pAKT, p=0.04; pERK1/2, p=0.03). This study highlights spatial and temporal cancer-associated expression alterations in the molecular field of injury of early stage NSCLC patients after definitive surgery that warrant further validation in independent studies.
  Cancer Prevention Research 10/2012; · 4.91 Impact Factor
• Article: Proteomic Profiling Identifies Dysregulated Pathways in Small Cell Lung Cancer and Novel Therapeutic Targets Including PARP1.

  Lauren Averett Byers, Jing Wang, Monique B Nilsson, Junya Fujimoto, Pierre Saintigny, John Yordy, Uma Giri, Michael Peyton, You Hong Fan, Lixia Diao, [......], Bonnie S Glisson, Neda Kalhor, Ignacio I Wistuba, Luc Girard, Scott M Lippman, Gordon B Mills, Kevin R Coombes, John N Weinstein, John D Minna, John V Heymach
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  ABSTRACT: Small cell lung cancer (SCLC) is an aggressive malignancy distinct from non-small cell lung cancer (NSCLC) in its metastatic potential and treatment response. Using an integrative proteomic and transcriptomic analysis, we investigated molecular differences contributing to the distinct clinical behavior of SCLCs and NSCLCs. SCLCs showed lower levels of several receptor tyrosine kinases and decreased activation of phosphoinositide 3-kinase (PI3K) and Ras/mitogen-activated protein (MAP)/extracellular signal-regulated kinase (ERK) kinase (MEK) pathways but significantly increased levels of E2F1-regulated factors including enhancer of zeste homolog 2 (EZH2), thymidylate synthase, apoptosis mediators, and DNA repair proteins. In addition, PARP1, a DNA repair protein and E2F1 co-activator, was highly expressed at the mRNA and protein levels in SCLCs. SCLC growth was inhibited by PARP1 and EZH2 knockdown. Furthermore, SCLC was significantly more sensitive to PARP inhibitors than were NSCLCs, and PARP inhibition downregulated key components of the DNA repair machinery and enhanced the efficacy of chemotherapy.
  Cancer discovery. 09/2012; 2(9):798-811.
• Article: Molecular aspects of thymic carcinoma.

  Annikka Weissferdt, Ignacio I Wistuba, Cesar A Moran
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  ABSTRACT: Thymic carcinomas are tumors of the anterior mediastinum derived from the epithelial cells of the thymic gland. Due to their low incidence they are often investigated in combination with thymomas under the rubric of "thymic epithelial neoplasms" and studies exclusively addressing thymic carcinomas are sparse. Thymic carcinomas are characterized by their histologic variability, often resembling tumors seen in other organ systems. This morphologic variation coupled with their rarity has prevented large scale research of these tumors and little is known about the etiology, biologic behavior or best treatment for thymic carcinoma. In recent years, attempts have been made to investigate the molecular characteristics of these tumors in the hope that molecular profiling can be used to predict the prognosis or lead to the development of new treatment strategies. Herein we provide an overview of the recent advances of the molecular analysis of thymic carcinoma with particular emphasis on the potential use for molecularly targeted therapies.
  Lung cancer (Amsterdam, Netherlands) 08/2012; 78(2):127-32. · 3.14 Impact Factor
• Article: Tissue platinum concentration and tumor response in non-small-cell lung cancer.

  Eric S Kim, J Jack Lee, Guangan He, Chi-Wan Chow, Junya Fujimoto, Neda Kalhor, Stephen G Swisher, Ignacio I Wistuba, David J Stewart, Zahid H Siddik
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  ABSTRACT: PURPOSE Platinum resistance is a major limitation in the treatment of advanced non-small-cell lung cancer (NSCLC). Reduced intracellular drug accumulation is one of the most consistently identified features of platinum-resistant cell lines, but clinical data are limited. We assessed the effects of tissue platinum concentrations on response and survival in NSCLC. PATIENTS AND METHODS We measured total platinum concentrations by flameless atomic absorption spectrophotometry in 44 archived fresh-frozen NSCLC specimens from patients who underwent surgical resection after neoadjuvant platinum-based chemotherapy. Tissue platinum concentration was correlated with percent reduction in tumor size on post- versus prechemotherapy computed tomography scans. The relationship between tissue platinum concentration and survival was assessed by univariate and multicovariate Cox proportional hazards regression model analysis and Kaplan-Meier analysis. Results Tissue platinum concentration correlated significantly with percent reduction in tumor size (P < .001). The same correlations were seen with cisplatin, carboplatin, and all histology subgroups. Furthermore, there was no significant impact of potential variables such as number of cycles and time lapse from last chemotherapy on platinum concentration. Patients with higher platinum concentration had longer time to recurrence (P = .034), progression-free survival (P = .018), and overall survival (P = .005) in the multicovariate Cox model analysis after adjusting for number of cycles. CONCLUSION This clinical study established a relationship between tissue platinum concentration and response in NSCLC. It suggests that reduced platinum accumulation might be an important mechanism of platinum resistance in the clinical setting. Further studies investigating factors that modulate intracellular platinum concentration are warranted.
  Journal of Clinical Oncology 08/2012; 30(27):3345-52. · 18.37 Impact Factor
• Article: Global Evaluation of Eph Receptors and Ephrins in Lung Adenocarcinomas Identifies EphA4 as an Inhibitor of Cell Migration and Invasion.

  Pierre Saintigny, Shaohua Peng, Li Zhang, Banibrata Sen, Ignacio I Wistuba, Scott M Lippman, Luc Girard, John D Minna, John V Heymach, Faye M Johnson
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  ABSTRACT: The Eph family of receptors is the largest family of receptor tyrosine kinases, but it remains poorly studied in lung cancer. We aimed to systematically explore the human Eph receptors and their ligands, the ephrins, in lung adenocarcinoma. The prognostic impact of Eph receptor and ephrin gene expression was analyzed using 2 independent cohorts of lung adenocarcinoma. Gene expression profiles in lung adenocarcinoma compared with normal adjacent lung were studied in 3 independent cohorts and in cell lines. Gene expression profiles were validated with quantitative polymerase chain reaction (qPCR) and Western blotting in cell lines. Functional studies to assess the role of Eph receptor A4 (EphA4) were carried out in vitro. The biological effects of EphA4 in lung cancer cell lines were assayed following overexpression and knockdown. Of the 11 Eph receptors and 8 ephrins analyzed, only EphA4 and ephrin A1 gene expression were consistently associated with an improved outcome in patients with lung adenocarcinoma. Expression levels of EphA4 by microarray correlated well with expression levels measured by qPCR and Western blotting. EphA4 overexpression reduced cell migration and invasion but did not affect cell cycle, apoptosis, or drug sensitivity. Surprisingly, EphA4 was expressed at higher levels in cancer compared with non-cancer tissues and cell lines. EphA4 gene expression is associated with an improved outcome in patients with resected lung adenocarcinoma, possibly by affecting cancer cell migration and invasion. Mol Cancer Ther; 11(9); 2021-32. ©2012 AACR.
  Molecular Cancer Therapeutics 07/2012; 11(9):2021-32. · 5.23 Impact Factor
• Article: Differential expression of somatostatin receptors 1-5 in neuroendocrine carcinoma of the lung.

  Koji Tsuta, Ignacio I Wistuba, Cesar A Moran
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  ABSTRACT: The majority of neuroendocrine carcinomas (NECs) express somatostatin (SST) receptors (SSTRs). However, the expression of all 5 SSTR subtypes in pulmonary NECs has not been reported. We performed immunohistochemical analysis of all 5 SSTR subtypes (including the SSTR2A and 2B isoforms). In typical carcinoids, immunoexpression of SSTR 1, 2A, 2B, 3, 4, and 5 was observed in 47/56 (79.7%), 57/58 (96.6%), 39/59 (66.1%), 28/57 (49.1%), 3/58 (5.2%), and 0/57 cases, respectively. In atypical carcinoids, immunoexpression of SSTR 1, 2A, 2B, 3, 4, and 5 was observed in 7/9 (77.8%), 7/9 (77.8%), 7/9 (77.8%), 3/9 (33.3%), 0/9, and 0/9 cases, respectively. In large cell NECs, immunoexpression of SSTR types 1, 2A, 2B, 3, 4, and 5 was observed in 12/20 (60%), 12/20 (60%), 6/20 (30%), 8/20 (40%), 0/20, and 3/20 (15%) cases, respectively. In small-cell carcinomas, immunoexpression of SSTR types 1, 2A, 2B, 3, 4, and 5 was observed in 16/54 (27.6%), 40/56 (69%), 14/56 (24.1%), 9/56 (15.5%), 0/58, and 2/55 (3.4%) cases, respectively. Except for SSTR5, all SSTRs showed a tendency toward decreased expression in well- to poorly differentiated NECs. We believe that these findings indicate important implications for the future of SST analog therapy.
  Pathology - Research and Practice 07/2012; 208(8):470-4. · 1.21 Impact Factor
• Article: Personalizing Lung Cancer Prevention Through a Reverse Migration Strategy.

  Kathryn A Gold, Edward S Kim, Ignacio I Wistuba, Waun K Hong
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  ABSTRACT: Lung cancer is the deadliest cancer in the United States and worldwide. Tobacco use is the one of the primary causes of lung cancer and smoking cessation is an important step towards prevention, but patients who have quit smoking remain at risk for lung cancer. Finding pharmacologic agents to prevent lung cancer could potentially save many lives. Unfortunately, despite extensive research, there are no known effective chemoprevention agents for lung cancer. Clinical trials in the past, using agents without a clear target in an unselected population, have shown pharmacologic interventions to be ineffective or even harmful. We propose a new approach to drug development in the chemoprevention setting: reverse migration, that is, drawing on our experience in the treatment of advanced cancer to bring agents, biomarkers, and study designs into the prevention setting. By identifying molecular drivers of lung neoplasia and using matched targeted agents, we hope to personalize therapy to each individual to develop more effective, tolerable chemoprevention. Also, advances in risk modeling, using not only clinical characteristics but also biomarkers, may help us to select patients better for chemoprevention efforts, thus sparing patients at low risk for cancer the potential toxicities of treatment. Our institution has experience with biomarker-driven clinical trials, as in the recently reported Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) trial, and we now propose to bring this trial design into the prevention setting.
  Topics in current chemistry 07/2012; · 4.29 Impact Factor