Ignacio I Wistuba

Publications (177)1078.52 Total impact

• Article: Map2k4 functions as a tumor suppressor in lung adenocarcinoma and inhibits tumor cell invasion by decreasing peroxisome proliferator-activated receptor γ2 expression.

  Young-Ho Ahn, Yanan Yang, Don L Gibbons, Chad J Creighton, Fei Yang, Ignacio I Wistuba, Wei Lin, Nishan Thilaganathan, Cristina A Alvarez, Jonathon Roybal, Elizabeth J Goldsmith, Cathy Tournier, Jonathan M Kurie
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  ABSTRACT: MAP2K4 encodes a dual-specificity kinase (mitogen-activated protein kinase kinase 4, or MKK4) that is mutated in a variety of human malignancies, but the biochemical properties of the mutant kinases and their roles in tumorigenesis have not been fully elucidated. Here we showed that 8 out of 11 cancer-associated MAP2K4 mutations reduce MKK4 protein stability or impair its kinase activity. On the basis of findings from bioinformatic studies on human cancer cell lines with homozygous MAP2K4 loss, we posited that MKK4 functions as a tumor suppressor in lung adenocarcinomas that develop in mice owing to expression of mutant Kras and Tp53. Conditional Map2k4 inactivation in the bronchial epithelium of mice had no discernible effect alone but increased the multiplicity and accelerated the growth of incipient lung neoplasias induced by oncogenic Kras. MKK4 suppressed the invasion and metastasis of Kras-Tp53-mutant lung adenocarcinoma cells. MKK4 deficiency increased peroxisomal proliferator-activated receptor γ2 (PPARγ2) expression through noncanonical MKK4 substrates, and PPARγ2 enhanced tumor cell invasion. We conclude that Map2k4 functions as a tumor suppressor in lung adenocarcinoma and inhibits tumor cell invasion by decreasing PPARγ2 levels.
  Molecular and cellular biology 09/2011; 31(21):4270-85. · 6.06 Impact Factor
• Article: Activating enhancer-binding protein-2β nucleolar localization predicts poor survival after stage I non-small cell lung cancer resection.

  Min P Kim, Ying Chen, B Nebiyou Bekele, Adriana Lopez, Abha Khanna, Jie Qing Chen, Margaret R Spitz, Carmen Behrens, Luisa Solis, Marnie Wismach, Lin Ji, Ignacio I Wistuba, Jack A Roth, Ruth L Katz
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  ABSTRACT: Activating enhancer-binding protein-2β (AP2β) is a transcription factor involved in apoptosis. The purpose of the current study was to assess the cellular location and level of AP2β in non-small cell lung cancer (NSCLC) and normal lung tissue and investigate whether the level and localization of AP2β expression is predictive of overall survival in patients with stage I NSCLC. We performed immunohistochemical analysis of tissue microarrays (TMAs) prepared from stage I NSCLC specimens with adjacent normal lung tissue from two independent sets of patients who underwent lung resection with curative intent at our institution. The AP2β intensity was assessed in TMAs, and AP2β staining patterns were classified as either diffuse or nucleolar in the TMAs. The AP2β intensity and localization were analyzed for correlation with patients' survival. Immunohistochemical analysis of TMAs showed that the intensity of AP2β immunohistochemical staining did not correlate with overall survival. When location of AP2β was analyzed in TMAs, all of the normal lung tissue had diffuse pattern of AP2β. In the first set of NSCLC, patients with nucleolar pattern had a significantly lower 5-year survival rate than patients with diffuse pattern (67% versus 100%; p=0.004); this finding was confirmed in the second set (64% versus 91%; p=0.02). Multivariate analysis revealed that nucleolar pattern was an independent predictor of poor overall survival in both sets. The AP2β, which is located in the nucleoplasm in normal lung tissue, is found in either nucleoplasm or nucleoli in NSCLC. The patients with AP2β in the nucleoli had poor survival compared with patients with AP2β in the cytoplasm.
  The Annals of thoracic surgery 09/2011; 92(3):1044-50. · 3.74 Impact Factor
• Article: Phase II trials of imatinib mesylate and docetaxel in patients with metastatic non-small cell lung cancer and head and neck squamous cell carcinoma.

  Anne S Tsao, Suyu Liu, Junya Fujimoto, Ignacio I Wistuba, J Jack Lee, Edith M Marom, Chusilp Charnsangavej, Frank V Fossella, Hai T Tran, George R Blumenschein, Vassiliki Papadimitrakopoulou, Merrill S Kies, Waun K Hong, David J Stewart
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  ABSTRACT: Two phase II clinical trials in the aerodigestive tumors were undertaken to evaluate the efficacy of imatinib mesylate-docetaxel. We hypothesized that imatinib mesylate would inhibit platelet-derived growth factor receptor (PDGFR) on pericytes and increase docetaxel uptake into tumor cells for an additive antitumor effect. Baseline tumor specimens, serum, and perfusion computed tomography (CT) scans were obtained for supportive evaluation. Eligible patients with metastatic non-small cell lung cancer (NSCLC) treated with 1 prior therapy and chemonaive patients with head and neck squamous cell carcinoma (HNSCC) were enrolled in separate trials, which administered both docetaxel (60 mg/m every 3 weeks) and oral imatinib mesylate (400 mg daily). Both trials used interim analyses for efficacy and safety. Twenty-two patients with NSCLC and seven patients with HNSCC were enrolled. Both trials were closed early due to lack of efficacy, significant toxicity, and a potential antagonistic effect. In the NSCLC study, the response rate was 4.5%, median progression-free survival (PFS) 7.9 weeks, and overall survival 35.6 weeks. The HNSCC trial yielded a response rate 0%, PFS 8.8 weeks, and overall survival 34.7 weeks. Baseline NSCLC tumor immunohistochemical biomarker analyses indicated that lower expression of stromal PDGFRβ correlated with a better PFS, whereas stromal PDGFRα and tumor cell PDGFRβ were associated with a worse clinical outcome when treated with imatinib mesylate-docetaxel. We do not recommend further investigation of this regimen in the aerodigestive tumors. Future investigations in PDGFR tyrosine kinase inhibitors should be used with caution in combination with taxanes and validation of the potential predictive or prognostic biomarkers stromal PDGFRα/β, and tumor cell PDGFRβ are needed.
  Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 09/2011; 6(12):2104-11. · 4.55 Impact Factor
• Article: Clinicopathological and immunohistochemical analysis of spindle-cell carcinoid tumour of the lung.

  Koji Tsuta, Neda Kalhor, Ignacio I Wistuba, Cesar A Moran
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  ABSTRACT: Aims: To analyse the clinicopathological features and immunohistchemical profile of spindle-cell carcinoid tumours (SCCT) of the lung. METHODS AND RESULTS: Using a cut-off value of ≥ 50% spindle cells for defining SCCT, 13 were indentified among 80 consecutively resected carcinoid cases. SCCTs are asymptomatic and are peripherally located, well-demarcated tumours. Tumour cells were composed of elongated spindle cells, with scant to moderate amounts of cytoplasm and uniform nuclei with fine granular chromatin. Immunohistochemical analysis revealed that all 13 cases were positive for three neuroendocrine markers (chromogranin A, synaptophysin and CD56). Four tumours (30.7%) were positive for broad-spectrum cytokeratin (CK) and nine tumours (69.2%) were positive for thyroid transcription factor 1. All epithelial components were negative for vimentin, but 12 tumours (92.3%) were positive for stellate-shaped cells (so-called sustentacular cells). CONCLUSIONS: SCCTs are clinically asymptomatic, peripherally located, well-demarcated tumours, and patients with SCCTs have a favourable outcome. The immunoreactivity pattern of SCCT (low reactivity of broad-spectrum CK and reactivity for vimentin in intratumoral sustentacular cells) might result in a misdiagnosis of SCCT as mesenchymal tumour; therefore, pathologists need to be familiar with this pattern.
  Histopathology 09/2011; 59(3):526-36. · 3.08 Impact Factor
• Article: Mechanistic contribution of ubiquitous 15-lipoxygenase-1 expression loss in cancer cells to terminal cell differentiation evasion.

  Micheline J Moussalli, Yuanqing Wu, Xiangsheng Zuo, Xiu L Yang, Ignacio Ivan Wistuba, Maria G Raso, Jeffrey S Morris, Jessica L Bowser, John D Minna, Reuben Lotan, Imad Shureiqi
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  ABSTRACT: Loss of terminal cell differentiation promotes tumorigenesis. 15-Lipoxygenase-1 (15-LOX-1) contributes to terminal cell differentiation in normal cells. The mechanistic significance of 15-LOX-1 expression loss in human cancers to terminal cell differentiation suppression is unknown. In a screen of 128 cancer cell lines representing more than 20 types of human cancer, we found that 15-LOX-1 mRNA expression levels were markedly lower than levels in terminally differentiated cells. Relative expression levels of 15-LOX-1 (relative to the level in terminally differentiated primary normal human-derived bronchial epithelial cells) were lower in 79% of the screened cancer cell lines than relative expression levels of p16 (INK4A), which promotes terminal cell differentiation and is considered one of the most commonly lost tumor suppressor genes in cancer cells. 15-LOX-1 was expressed during terminal differentiation in three-dimensional air-liquid interface cultures, and 15-LOX-1 expression and terminal differentiation occurred in immortalized nontransformed bronchial epithelial but not in lung cancer cell lines. 15-LOX-1 expression levels were lower in human tumors than in paired normal lung epithelia. Short hairpin RNA-mediated downregulation of 15-LOX-1 in Caco-2 cells blocked enterocyte-like differentiation, disrupted tight junction formation, and blocked E-cadherin and ZO-1 localization to the cell wall membrane. 15-LOX-1 episomal expression in Caco-2 and HT-29 colon cancer cells induced differentiation. Our findings indicate that 15-LOX-1 downregulation in cancer cells is an important mechanism for terminal cell differentiation dysregulation and support the potential therapeutic utility of 15-LOX-1 reexpression to inhibit tumorigenesis.
  Cancer Prevention Research 08/2011; 4(12):1961-72. · 4.91 Impact Factor
• Article: Using the mitosis-specific marker anti-phosphohistone H3 to assess mitosis in pulmonary neuroendocrine carcinomas.

  Koji Tsuta, Diane C Liu, Neda Kalhor, Ignacio I Wistuba, Cesar A Moran
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  ABSTRACT: Counting mitotic figures (MFs) is one of the essential factors for determining the histologic grade of pulmonary neuroendocrine carcinoma (NEC). We analyzed MFs by using a mitotic-specific antibody of phosphohistone H3 (PHH3) in 113 lung NECs (66 typical carcinoids [TCs], 12 atypical carcinoids [ACs], 20 large cell NECs [LCNECs], and 15 small cell lung carcinomas [SCLCs]). Subdivided by histologic subtype, the mean PHH3-stained MFs (mPHMFs) were 0.09 per high-power field (hpf) in TCs, 0.39/hpf in ACs, 7.84/hpf in LCNECs, and 9.42 in SCLCs. From the 5-year overall survival rate for mPHMFs, an mPHMF of more than 1.0 was the best threshold in all NECs and an mPHMF of more than 0.4 was the best threshold for differentiating ACs from TCs. These values correspond to 4/10 hpf and 10/10 hpf. We showed that the PHH3-based mitosis-counting method is a reliable, easy method for counting mitoses in pulmonary NECs.
  American Journal of Clinical Pathology 08/2011; 136(2):252-9. · 2.60 Impact Factor
• Article: Robust gene expression signature from formalin-fixed paraffin-embedded samples predicts prognosis of non-small-cell lung cancer patients.

  Yang Xie, Guanghua Xiao, Kevin R Coombes, Carmen Behrens, Luisa M Solis, Gabriela Raso, Luc Girard, Heidi S Erickson, Jack Roth, John V Heymach, Cesar Moran, Kathy Danenberg, John D Minna, Ignacio I Wistuba
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  ABSTRACT: The requirement of frozen tissues for microarray experiments limits the clinical usage of genome-wide expression profiling by using microarray technology. The goal of this study is to test the feasibility of developing lung cancer prognosis gene signatures by using genome-wide expression profiling of formalin-fixed paraffin-embedded (FFPE) samples, which are widely available and provide a valuable rich source for studying the association of molecular changes in cancer and associated clinical outcomes. We randomly selected 100 Non-Small-Cell lung cancer (NSCLC) FFPE samples with annotated clinical information from the UT-Lung SPORE Tissue Bank. We microdissected tumor area from FFPE specimens and used Affymetrix U133 plus 2.0 arrays to attain gene expression data. After strict quality control and analysis procedures, a supervised principal component analysis was used to develop a robust prognosis signature for NSCLC. Three independent published microarray datasets were used to validate the prognosis model. This study showed that the robust gene signature derived from genome-wide expression profiling of FFPE samples is strongly associated with lung cancer clinical outcomes and can be used to refine the prognosis for stage I lung cancer patients, and the prognostic signature is independent of clinical variables. This signature was validated in several independent studies and was refined to a 59-gene lung cancer prognosis signature. We conclude that genome-wide profiling of FFPE lung cancer samples can identify a set of genes whose expression level provides prognostic information across different platforms and studies, which will allow its application in clinical settings.
  Clinical Cancer Research 07/2011; 17(17):5705-14. · 7.74 Impact Factor
• Article: Increased VEGFR-2 gene copy is associated with chemoresistance and shorter survival in patients with non-small-cell lung carcinoma who receive adjuvant chemotherapy.

  Fei Yang, Ximing Tang, Erick Riquelme, Carmen Behrens, Monique B Nilsson, Uma Giri, Marileila Varella-Garcia, Lauren A Byers, Heather Y Lin, Jing Wang, Maria G Raso, Luc Girard, Kevin Coombes, J Jack Lee, Roy S Herbst, John D Minna, John V Heymach, Ignacio I Wistuba
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  ABSTRACT: VEGF receptor-2 (VEGFR-2 or kinase insert domain receptor; KDR) is a known endothelial target also expressed in NSCLC tumor cells. We investigated the association between alterations in the KDR gene and clinical outcome in patients with resected non-small-cell lung carcinoma (NSCLC; n = 248). KDR copy number gains (CNG), measured by quantitative PCR and fluorescence in situ hybridization, were detected in 32% of tumors and associated with significantly higher KDR protein and higher microvessel density than tumors without CNGs. KDR CNGs were also associated with significantly increased risk of death (HR = 5.16; P = 0.003) in patients receiving adjuvant platinum-based chemotherapy, but no differences were observed in patients not receiving adjuvant therapy. To investigate potential mechanisms for these associations, we assessed NSCLC cell lines and found that KDR CNGs were significantly associated with in vitro resistance to platinum chemotherapy as well as increased levels of nuclear hypoxia inducible factor-1α (HIF-1α) in both NSCLC tumor specimens and cell lines. Furthermore, KDR knockdown experiments using small interfering RNA reduced platinum resistance, cell migration, and HIF-1α levels in cells bearing KDR CNGs, providing evidence for direct involvement of KDR. No KDR mutations were detected in exons 7, 11, and 21 by PCR-based sequencing; however, two variant single nucleotide polymorphism genotypes were associated with favorable overall survival in adenocarcinoma patients. Our findings suggest that tumor cell KDR CNGs may promote a more malignant phenotype including increased chemoresistance, angiogenesis, and HIF-1α levels, and that KDR CNGs may be a useful biomarker for identifying patients at high risk for recurrence after adjuvant therapy, a group that may benefit from VEGFR-2 blockade.
  Cancer Research 07/2011; 71(16):5512-21. · 7.86 Impact Factor
• Article: The BATTLE to personalize lung cancer prevention through reverse migration.

  Kathryn A Gold, Edward S Kim, J Jack Lee, Ignacio I Wistuba, Carol J Farhangfar, Waun Ki Hong
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  ABSTRACT: Agents can enter clinical development for cancer prevention either initially or after previous development for a different indication, such as arthritis, with both approaches consuming many years of development before an agent is fully evaluated for cancer prevention. We propose the following, third approach: reverse migration, that is, importing agents, targets, and study designs to personalize interventions and concepts developed in advanced cancer to the setting of cancer prevention. Importing these "ready-made" features from therapy will allow reverse migration to streamline preventive agent development. We recently reported the Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) trial of personalized lung cancer therapy and now propose the reverse migration development of personalized lung cancer prevention based on the BATTLE model.
  Cancer Prevention Research 07/2011; 4(7):962-72. · 4.91 Impact Factor
• Article: Inhibitor of differentiation-1 as a novel prognostic factor in NSCLC patients with adenocarcinoma histology and its potential contribution to therapy resistance.

  Mariano Ponz-Sarvisé, Paul A Nguewa, María J Pajares, Jackeline Agorreta, María D Lozano, Miriam Redrado, Ruben Pio, Carmen Behrens, Ignacio I Wistuba, Carlos E García-Franco, Jesús García-Foncillas, Luis M Montuenga, Alfonso Calvo, Ignacio Gil-Bazo
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  ABSTRACT: High inhibitor of differentiation-1 (Id1) levels have been found in some tumor types. We aimed to study Id1 levels and their prognostic impact in a large series of stages I to IV non-small cell lung cancer (NSCLC) patients. Experiments in cell lines and cells derived from malignant pleural effusions (MPE) were also carried out. A total of 346 NSCLC samples (three different cohorts), including 65 matched nonmalignant tissues, were evaluated for Id1 expression by using immunohistochemistry. Additional data from a fourth cohort including 111 patients were obtained for Id1 mRNA expression analysis by using publicly available microarrays. In vitro proliferation assays were conducted to characterize the impact of Id1 on growth and treatment sensitivity. Significantly higher Id1 protein levels were found in tumors compared with normal tissues (P < 0.001) and in squamous carcinomas compared with adenocarcinomas (P < 0.001). In radically treated stages I to III patients and stage IV patients treated with chemotherapy, higher Id1 levels were associated with a shorter disease-free survival and overall survival in adenocarcinoma patients in a log-rank test. A Cox model confirmed the independent prognostic value of Id1 levels for both stages I to III and stage IV patients. In silico analysis confirmed a correlation between higher Id1 mRNA levels and poor prognosis for adenocarcinoma subjects. In vitro Id1 silencing in radio/chemotherapy-resistant adenocarcinoma cells from MPEs restored sensitivity to both therapies. In our series, Id1 levels showed an independent prognostic value in patients with adenocarcinoma, regardless of the stage. Id1 silencing may sensitize adenocarcinoma cells to radiotherapy and chemotherapy.
  Clinical Cancer Research 06/2011; 17(12):4155-66. · 7.74 Impact Factor
• Article: Delineation of a cellular hierarchy in lung cancer reveals an oncofetal antigen expressed on tumor-initiating cells.

  Marc Damelin, Kenneth G Geles, Maximillian T Follettie, Ping Yuan, Michelle Baxter, Jonathon Golas, John F DiJoseph, Maha Karnoub, Shuguang Huang, Veronica Diesl, [......], Philip R Hamann, Deborah Evans, Douglas Armellino, Kiran Khandke, Kimberly Marquette, Lioudmila Tchistiakova, Erwin R Boghaert, Robert T Abraham, Ignacio I Wistuba, Bin-Bing S Zhou
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  ABSTRACT: Poorly differentiated tumors in non-small cell lung cancer (NSCLC) have been associated with shorter patient survival and shorter time to recurrence following treatment. Here, we integrate multiple experimental models with clinicopathologic analysis of patient tumors to delineate a cellular hierarchy in NSCLC. We show that the oncofetal protein 5T4 is expressed on tumor-initiating cells and associated with worse clinical outcome in NSCLC. Coexpression of 5T4 and factors involved in the epithelial-to-mesenchymal transition were observed in undifferentiated but not in differentiated tumor cells. Despite heterogeneous expression of 5T4 in NSCLC patient-derived xenografts, treatment with an anti-5T4 antibody-drug conjugate resulted in complete and sustained tumor regression. Thus, the aggressive growth of heterogeneous solid tumors can be blocked by therapeutic agents that target a subpopulation of cells near the top of the cellular hierarchy.
  Cancer Research 06/2011; 71(12):4236-46. · 7.86 Impact Factor
• Article: The BATTLE trial: personalizing therapy for lung cancer.

  Edward S Kim, Roy S Herbst, Ignacio I Wistuba, J Jack Lee, George R Blumenschein, Anne Tsao, David J Stewart, Marshall E Hicks, Jeremy Erasmus, Sanjay Gupta, [......], Hai T Tran, Bruce E Johnson, John V Heymach, Li Mao, Frank Fossella, Merrill S Kies, Vassiliki Papadimitrakopoulou, Suzanne E Davis, Scott M Lippman, Waun K Hong
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  ABSTRACT: The Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) trial represents the first completed prospective, biopsy-mandated, biomarker-based, adaptively randomized study in 255 pretreated lung cancer patients. Following an initial equal randomization period, chemorefractory non-small cell lung cancer (NSCLC) patients were adaptively randomized to erlotinib, vandetanib, erlotinib plus bexarotene, or sorafenib, based on relevant molecular biomarkers analyzed in fresh core needle biopsy specimens. Overall results include a 46% 8-week disease control rate (primary end point), confirm prespecified hypotheses, and show an impressive benefit from sorafenib among mutant-KRAS patients. BATTLE establishes the feasibility of a new paradigm for a personalized approach to lung cancer clinical trials. SIGNIFICANCE: The BATTLE study is the first completed prospective, adaptively randomized study in heavily pretreated NSCLC patients that mandated tumor profiling with "real-time" biopsies, taking a substantial step toward realizing personalized lung cancer therapy by integrating real-time molecular laboratory findings in delineating specific patient populations for individualized treatment.
  Cancer discovery. 06/2011; 1(1):44-53.
• Article: Cotargeting cyclin D1 starts a new chapter in lung cancer prevention and therapy.

  Edward S Kim, J Jack Lee, Ignacio I Wistuba
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  ABSTRACT: Lung cancer has limited effective therapy and no effective prevention. Cytotoxic chemotherapy has not improved when combined with the epidermal growth factor receptor (EGFR) inhibitor erlotinib (standard lung cancer therapy) or with the rexinoid bexarotene. Combining erlotinib and bexarotene, however, to cotarget cyclin D1 via the retinoid X receptor and EGFR was active preclinically in KRAS-driven lung cancer cells derived from transgenic mice and in two clinical studies in lung cancer (including wild-type EGFR tumors, with or without KRAS mutations), as reported in this issue of the journal by Dragnev and colleagues (beginning on page 818). These results, along with closely related clinical results of the BATTLE program, support the promise of this cotargeting approach for lung cancer prevention and therapy and of cyclin D1 as a predictive, personalizing marker for it.
  Cancer Prevention Research 06/2011; 4(6):779-82. · 4.91 Impact Factor
• Article: Immunohistochemical overexpression of platelet-derived growth factor receptor-beta (PDGFR-β) is associated with PDGFRB gene copy number gain in sarcomatoid non-small-cell lung cancer.

  Anne S Tsao, Wei Wei, Elisabetta Kuhn, Loreto Spencer, Luisa M Solis, Milind Suraokar, J Jack Lee, Waun Ki Hong, Ignacio I Wistuba
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  ABSTRACT: Sarcomatoid non-small cell lung cancer (NSCLC) is an uncommon histologic variant that has not been molecularly well-characterized. We conducted immunohistochemical and fluorescence in situ hybridization studies of PDGF-B/PDGFR-b on archived surgically resected specimens and showed high PDGFR-b IHC expression and gene copy number gain. Further studies are warranted to determine whether PDGFR-b is a feasible therapeutic target in this population. Sarcomatoid non-small cell lung cancer (NSCLC) is an uncommon histologic variant that has not been molecularly well-characterized. We hypothesized that the PDGF-B/PDGF-Rβ pathway may be dysregulated in sarcomatoid lung cancer. We conducted immunohistochemical (IHC) and gene copy number gain studies of PDGF-B/PDGFR-β on archived surgically resected specimens, 43 sarcomatoid NSCLCs and 42 control NSCLCs that were age, gender and stage-matched. Biomarkers were correlated to patient demographics, tumor characteristics, and survival. Sarcomatoid tumors had higher PDGFR-β IHC expression than control NSCLC (median score 2.69 vs. 1.93; P < 0.0001). No difference was seen between the two groups of PDGF-B IHC expression; and neither PDGF-B nor PDGFR-β IHC levels correlated with gender, age, clinical or pathologic TNM status, or overall survival. PDGFRB gene copy number was evaluated by FISH using three ways: presence of amplification, gene copy number gain, and gene copy ratio between tumor and normal tissue. PDGFRB gene copy number gain was associated with sarcomatoid histology (P = 0.006), lower clinical and pathologic T-stage (P = 0.07, P = 0.048), and higher pathologic N-stage (P = 0.013). Sarcomatoid NSCLC patients (P = 0.006) and female patients (P = 0.03) had higher gene copy ratios above 1.83. Higher PDGFR-β IHC expression in tumor cells was associated with gene copy number gain (P = 0.021) and higher gene copy ratio status (P = 0.005). This is the first study to demonstrate high PDGFR-β IHC expression and gene copy number gain in sarcomatoid NSCLC tumors and suggests that further studies are warranted to determine whether PDGFR-β is a feasible therapeutic target in this population.
  Clinical Lung Cancer 05/2011; 12(6):369-74. · 2.94 Impact Factor
• Article: Methodological and practical challenges for personalized cancer therapies

  Ignacio I. Wistuba, Juri G. Gelovani, J|[ouml]|rg J. Jacoby, Suzanne E. Davis, Roy S. Herbst
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  ABSTRACT: Many experts agree that personalized cancer medicine, defined here as treatment based on the molecular characteristics of a tumor from an individual patient, has great potential in the therapy of many types of cancer. Although targeted therapy agents are increasingly available for clinical applications, many of these promising drugs have produced disappointing results when tested in clinical trials, indicating that there are many challenges that must be addressed to advance this field. We propose that a new generation of clinical trials requiring biopsies to obtain relevant tumor specimens, as well as novel statistical designs, will be essential to improve treatment outcomes. However, these novel clinical trials will only be successful if appropriate biomarkers are identified to help guide the selection of the most beneficial treatments for the participating patients. Although biomarkers based on single gene mutations are the most commonly used in clinical applications today, gene-expression or protein-expression 'signatures' and new imaging technologies have the potential to play important roles as biomarkers in the future. Therefore, it is of crucial importance that we identify and resolve existing challenges that may impede the rapid identification and translation of validated biomarkers with acceptable sensitivity and specificity from the laboratory to the clinic. These challenges include limitations of current biomarker development methodologies and regulatory and reimbursement policies and practices.
  Nature Reviews Clinical Oncology 03/2011; 8(3):135-141. · 11.96 Impact Factor
• Article: Methodological and practical challenges for personalized cancer therapies.

  Ignacio I Wistuba, Juri G Gelovani, Jörg J Jacoby, Suzanne E Davis, Roy S Herbst
  [show abstract] [hide abstract]
  ABSTRACT: Many experts agree that personalized cancer medicine, defined here as treatment based on the molecular characteristics of a tumor from an individual patient, has great potential in the therapy of many types of cancer. Although targeted therapy agents are increasingly available for clinical applications, many of these promising drugs have produced disappointing results when tested in clinical trials, indicating that there are many challenges that must be addressed to advance this field. We propose that a new generation of clinical trials requiring biopsies to obtain relevant tumor specimens, as well as novel statistical designs, will be essential to improve treatment outcomes. However, these novel clinical trials will only be successful if appropriate biomarkers are identified to help guide the selection of the most beneficial treatments for the participating patients. Although biomarkers based on single gene mutations are the most commonly used in clinical applications today, gene-expression or protein-expression 'signatures' and new imaging technologies have the potential to play important roles as biomarkers in the future. Therefore, it is of crucial importance that we identify and resolve existing challenges that may impede the rapid identification and translation of validated biomarkers with acceptable sensitivity and specificity from the laboratory to the clinic. These challenges include limitations of current biomarker development methodologies and regulatory and reimbursement policies and practices.
  Nature Reviews Clinical Oncology 03/2011; 8(3):135-41. · 11.96 Impact Factor
• Article: Differential impacts of insulin-like growth factor-binding protein-3 (IGFBP-3) in epithelial IGF-induced lung cancer development.

  Woo-Young Kim, Mi-Jung Kim, Hojin Moon, Ping Yuan, Jin-Soo Kim, Jong-Kyu Woo, Guangcheng Zhang, Young-Ah Suh, Lei Feng, Carmen Behrens, Carolyn S Van Pelt, Hyunseok Kang, J Jack Lee, Waun-Ki Hong, Ignacio I Wistuba, Ho-Young Lee
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  ABSTRACT: The IGF axis has been implicated in the risk of various cancers. We previously reported a potential role of tissue-derived IGF in lung tumor formation and progression. However, the role of IGF-binding protein (IGFBP)-3, a major IGFBP, on the activity of tissue-driven IGF in lung cancer development is largely unknown. Here, we show that IGF-I, but not IGF-II, protein levels in non-small-cell lung cancer (NSCLC) were significantly higher than those in normal and hyperplastic bronchial epithelium. We found that IGF-I and IGFBP-3 levels in NSCLC tissue specimens were significantly correlated with phosphorylated IGF-IR (pIGF-IR) expression. We investigated the impact of IGFBP-3 expression on the activity of tissue-driven IGF-I in lung cancer development using mice carrying lung-specific human IGF-I transgene (Tg), a germline-null mutation of IGFBP-3, or both. Compared with wild-type (BP3(+/+)) mice, mice carrying heterozygous (BP3(+/-)) or homozygous (BP3(-/-)) deletion of IGFBP-3 alleles exhibited decreases in circulating IGFBP-3 and IGF-I. Unexpectedly, IGF(Tg) mice with 50% of physiological IGFBP-3 (BP3(+/-); IGF(Tg)) showed higher levels of pIGF-IR/IR and a greater degree of spontaneous or tobacco carcinogen [4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone]-induced lung tumor development and progression than did the IGF(Tg) mice with normal (BP3(+/+;) IGF(Tg)) or homozygous deletion of IGFBP-3 (BP3(-/-); IGF(Tg)). These data show that IGF-I is overexpressed in NSCLC, leading to activation of IGF-IR, and that IGFBP-3, depending on its expression level, either inhibits or potentiates IGF-I actions in lung carcinogenesis.
  Endocrinology 03/2011; 152(6):2164-73. · 4.46 Impact Factor
• Article: Exponential decay nonlinear regression analysis of patient survival curves: preliminary assessment in non-small cell lung cancer.

  David J Stewart, Carmen Behrens, Jack Roth, Ignacio I Wistuba
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  ABSTRACT: For processes that follow first order kinetics, exponential decay nonlinear regression analysis (EDNRA) may delineate curve characteristics and suggest processes affecting curve shape. We conducted a preliminary feasibility assessment of EDNRA of patient survival curves. EDNRA was performed on Kaplan-Meier overall survival (OS) and time to relapse (TTR) curves for 323 patients with resected NSCLC and on OS and progression-free survival (PFS) curves from selected publications. In our resected patients, TTR curves were triphasic with a "cured" fraction of 60.7% (half-life [t1/2] >100,000 months), a rapidly relapsing group (7.4%, t1/2=5.9 months) and a slowly relapsing group (31.9%, t1/2=23.6 months). OS was uniphasic (t1/2=74.3 months), suggesting an impact of co-morbidities; hence, tumor molecular characteristics would more likely predict TTR than OS. Of 172 published curves analyzed, 72 (42%) were uniphasic, 92 (53%) were biphasic, 8 (5%) were triphasic. With first-line chemotherapy in advanced NSCLC, 87.5% of curves from 2 to 3 drug regimens were uniphasic vs. only 20% of those with best supportive care or 1 drug (p<0.001). 54% of curves from 2 to 3 drug regimens had convex rapid-decay phases vs. 0% with fewer agents (p<0.001). Curve convexities suggest that discontinuing chemotherapy after 3-6 cycles "synchronizes" patient progression and death. With postoperative adjuvant chemotherapy, the PFS rapid-decay phase accounted for a smaller proportion of the population than in controls (p=0.02) with no significant difference in rapid-decay t1/2, suggesting adjuvant chemotherapy may move a subpopulation of patients with sensitive tumors from the relapsing group to the cured group, with minimal impact on time to relapse for a larger group of patients with resistant tumors. In untreated patients, the proportion of patients in the rapid-decay phase increased (p=0.04) while rapid-decay t1/2 decreased (p=0.0004) with increasing stage, suggesting that higher stage may be associated with tumor cells that both grow more rapidly and have a higher probability of surviving metastatic processes than in early stage tumors. This preliminary assessment of EDNRA suggests that it may be worth exploring this approach further using more sophisticated, statistically rigorous nonlinear modelling approaches. Using such approaches to supplement standard survival analyses could suggest or support specific testable hypotheses.
  Lung cancer (Amsterdam, Netherlands) 02/2011; 71(2):217-23. · 3.14 Impact Factor
• Article: Evolving concepts in lung carcinogenesis.

  Brigitte N Gomperts, Avrum Spira, Pierre P Massion, Tonya C Walser, Ignacio I Wistuba, John D Minna, Steven M Dubinett
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  ABSTRACT: Lung carcinogenesis is a complex, stepwise process that involves the acquisition of genetic mutations and epigenetic changes that alter cellular processes, such as proliferation, differentiation, invasion, and metastasis. Here, we review some of the latest concepts in the pathogenesis of lung cancer and highlight the roles of inflammation, the "field of cancerization," and lung cancer stem cells in the initiation of the disease. Furthermore, we review how high throughput genomics, transcriptomics, epigenomics, and proteomics are advancing the study of lung carcinogenesis. Finally, we reflect on the potential of current in vitro and in vivo models of lung carcinogenesis to advance the field and on the areas of investigation where major breakthroughs will lead to the identification of novel chemoprevention strategies and therapies for lung cancer.
  Seminars in Respiratory and Critical Care Medicine 02/2011; 32(1):32-43. · 2.43 Impact Factor
• Article: Oncocytic neuroendocrine tumors of the lung: histopathologic spectrum and immunohistochemical analysis of 15 cases.

  Koji Tsuta, Neda Kalhor, Maria Gabriela Raso, Ignacio I Wistuba, Cesar A Moran
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  ABSTRACT: Oncocytic neuroendocrine tumor of the lung is rare. To reveal the clinicopathologic features of oncocytic neuroendocrine tumor, we reviewed surgical resections from 80 patients diagnosed with carcinoid tumors and 35 high-grade neuroendocrine carcinomas. We discovered 7 cases from the 80 carcinoid tumors and added 8 patients from personal consultation files. There were no statistically significant differences among the clinical features (such as age, location, and survival). Although most oncocytic neuroendocrine tumors were low-grade neuroendocrine carcinomas, we found that they could be of any grade. Tumor cells showed an ample amount of granular oncocytic cytoplasm and had a round-to-oval nucleus with coarse chromatin. Two cases mainly consisted of small-sized to medium-sized cells resembling plasma cells. This tumorous area intermingled with the conventional oncocytic area. Other histologic features were a large conspicuous nucleolus in 9 cases and the presence of giant cells in 8 cases. In the 80 carcinoid cases, bone formation (P = .034), the presence of giant cells (P = .021), and tumor cells with a conspicuous nucleolus (P = .021) were more frequently observed. Immunohistochemical analysis revealed that oncocytic cells were positive for antimitochondria antibody. In conclusion, most of the tumors were low-grade neuroendocrine carcinomas, but we found that oncocytic neuroendocrine tumor can display features of high-grade neuroendocrine carcinoma. The oncocytic change was induced by accumulation of mitochondria. Although this variant does not differ in clinical features of nononcocytic neuroendocrine tumors, histologic features of the oncocytic neuroendocrine tumor can be a potential cause of diagnostic error.
  Human pathology 02/2011; 42(4):578-85. · 3.03 Impact Factor