Samir E. Witta

Pompeu Fabra University

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Paul A. Bunn

University of Colorado Anschutz Medical Campus

Wilbur A. Franklin

University of Colorado Denver

Fred R. Hirsch

University of Colorado Anschutz Medical Campus

Christopher D. Coldren

University of Colorado Denver

Michio Sugita

University of Colorado Health

Razvan Lapadat

Loyola University Medical Center

Fred R. Hirsch

Icahn School of Medicine at Mount Sinai

Anna E. Barón

University of Colorado Anschutz Medical Campus

Barbara A. Helfrich

University of Colorado Anschutz Medical Campus

Mark W. Geraci

University of Pittsburgh

Cooperative Institutions

University of Colorado Denver

University of Colorado Health

University of Colorado Anschutz Medical Campus

University of Colorado Cancer Center

University of Colorado Boulder

The University of Texas MD Anderson Cancer Center

Gdańsk Medical University

University of Colorado Hospital

Texas Oncology

Istituti di Ricovero e Cura a Carattere Scientifico

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ErbB-3 expression is associated with E-cadherin and their coexpression restores response to gefitinib in non-small-cell lung cancer (NSCLC)

Annals of Oncology (2009)

Samir E. Witta Rafał Dziadziuszko Koichi Yoshida Karla Hedman Marileila Varella‐Garcia

Vorinostat

ErbB

10.1093/annonc/mdn703

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Citations (40)

Insulin-like Growth Factor Receptor 1 (IGF1R) Gene Copy Number Is Associated With Survival in Operable Non–Small-Cell Lung Cancer: A Comparison Between IGF1R Fluorescent In Situ Hybridization, Protein Expression, and mRNA Expression

Journal of Clinical Oncology (2010)

Rafał Dziadziuszko Daniel T. Merrick Samir E. Witta Adelita D. Mendoza Barbara Szostakiewicz

Purpose The purpose of this study was to characterize insulin-like growth factor-1 receptor (IGF1R) protein expression, mRNA expression, and gene copy number in surgically resected non–small-cell lung cancers (NSCLC) in relation to epidermal growth factor receptor (EGFR) protein expression, patient characteristics, and prognosis. Patients and Methods One hundred eighty-nine patients with NSCLC who underwent curative pulmonary resection were studied (median follow-up, 5.3 years). IGF1R protein expression was evaluated by immunohistochemistry (IHC) with two anti-IGF1R antibodies (n = 179). EGFR protein expression was assessed with PharmDx kit. IGF1R gene expression was evaluated using quantitative reverse transcription polymerase chain reaction (qRT-PCR) from 114 corresponding fresh-frozen samples. IGF1R gene copy number was assessed by fluorescent in situ hybridization using customized probes (n = 181). Results IGF1R IHC score was higher in squamous cell carcinomas versus other histologies (P < .001) and associated with stage (P = .03) but not survival (P = .46). IGF1R and EGFR protein expression showed significant correlation (r = 0.30; P < .001). IGF1R gene expression by qRT-PCR was higher in squamous cell versus other histologies (P = .006) and did not associate with other clinical features nor survival (P = .73). Employing criteria previously established for EGFR copy number, patients with IGF1R amplification/high polysomy (n = 48; 27%) had 3-year survival of 58%, patients with low polysomy (n = 87; 48%) had 3-year survival of 47% and patients with trisomy/disomy (n = 46; 25%) had 3-year survival of 35%, respectively (P = .024). Prognostic value of high IGF1R gene copy number was confirmed in multivariate analysis. Conclusion IGF1R protein expression is higher in squamous cell versus other histologies and correlates with EGFR expression. IGF1R protein and gene expression does not associate with survival, whereas high IGF1R gene copy number harbors positive prognostic value.

Polysomy

10.1200/jco.2009.24.6611

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XlPOU 2 is a potential regulator of Spemann’s Organizer

Development (1997)

Samir E. Witta Sheryl M. Sato

XIPOU 2, a member of the class III POU-domain family, is expressed initially at mid-blastula transition (MBT) and during gastrulation in the entire marginal zone mesoderm, including Spemann's Organizer (the Organizer). To identify potential targets of XIPOU 2, the interaction of XIPOU 2 with other genes co-expressed in the Organizer was examined by microinjecting XIPOU 2's mRNA into the lineage of cells that contributes to the Organizer, head mesenchyme and prechordal plate. XIPOU 2 suppresses the expression of a number of dorsal mesoderm-specific genes, including gsc, Xlim-1, Xotx2, noggin and chordin, but not Xnot. As a consequence of the suppression of dorsal mesoderm gene expression, bone morphogenetic factor-4 (Bmp-4), a potent inducer of ventral mesoderm, is activated in the Organizer. Gsc is a potential target of XIPOU 2. XIPOU 2 is capable of binding a class III POU protein binding site (CATTAAT) that is located within the gsc promoter, in the activin-inducible (distal) element. Furthermore, XIPOU 2 suppresses the activation of the gsc promoter by activin signaling. At the neurula and tailbud stages, dorsoanterior structures are affected: embryos displayed micropthalmia and the loss of the first branchial arch, as detected by the expression of pax-6, Xotx2 and en-2. By examining events downstream from the Wnt and chordin pathways, we determined that XIPOU 2, when overexpressed, acts specifically in the Organizer, downstream from GSK-3beta of the Wnt pathway and upstream from chordin. The interference in dorsalizing events caused by XIPOU 2 was rescued by chordin. Thus, in addition to its direct neuralizing ability, in a different context, XIPOU 2 has the potential to antagonize dorsalizing events in the Organizer.

Chordin

Neurula

10.1242/dev.124.6.1179

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Predicting clinical benefit from EGFR TKIs: Not all EGFR mutations are equal

Journal of Clinical Oncology (2006)

F. R. Hirsch Wilbur A. Franklin J. McCoy Federico Cappuzzo Marileila Varella‐Garcia

7072 Background: EGFR mutations are associated with better response and in some studies (mainly Asian) also with prolonged survival after gefitinib therapy in patients with advanced NSCLC. Although a number of mutations have been reported, most frequent are exon 19 or exon 21 mutations of the EGFR tyrosine kinase domain.Whether clinical outcomes differ by subtype of EGFR mutation has not been previously reported. Methods: Mutation analysis (as previously described) was performed in 157 of 204 patients with advanced NSCLC treated with gefitinib (250 mg or 500 mg) in 2 study cohorts (Italian study of Iressa Expanded Access Program and SWOG 0126). Fifty nanograms of genomic DNA was isolated from pretreatment tumors, amplified for EGFR exons 19 and 21 by touchdown hemi-nested polymerase chain reaction and sequenced in both sense and antisense directions. Results: EGFR mutations were found in 43 pts (27%). Overall, patients with EGFR mutations had a response rate of 39% versus 7% for those without (p ≤ 0.001), disease control rate of 52% versus 37% (p = 0.14), time to progression of 3 months in both groups and median survival of 13 months versus 11 months (p = 0.14). Patients with exon 19 mutations exclusively (N = 11) had better outcome than those with exon 21 mutations exclusively (N = 31), with response rates of 67% versus 20% (p = 0.02), median time to progression of 15 months versus 2 months, and median survival of 26 months versus 10 months. There was a difference in time to progression (11 months versus 3 months) and overall survival (median 26 months versus 11 months) between patients with and without exon 19 mutations, while no difference was apparent in these outcome measures in patients with and without exon 21 mutations. Sample size provided insufficient power for significance tests of differences in survival outcomes. Conclusions: Not all EGFR mutations are created equal. Mutations in exon 19 are more predictive of response and survival after gefitinib than exon 21 mutations. [Table: see text]

Progression-free survival

10.1200/jco.2006.24.18_suppl.7072

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Citations (25)

Supportive Care

Journal of Thoracic Oncology (2010)

Samir E. Witta

Pemetrexed

Clinical endpoint

Clinical Practice

10.1097/01.jto.0000391371.86753.d9

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Citations (1)

Biological Markers for Non–Small Cell Lung Cancer Patient Selection for Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy

Clinical Cancer Research (2006)

Paul A. Bunn Rafał Dziadziuszko Marileila Varella‐Garcia Wilbur A. Franklin Samir E. Witta

The selection of patients for tumor-specific therapies using molecular/biological properties of the patient's tumor has been a long tradition in breast cancer (e.g., estrogen receptor, progesterone receptor, and HER-2/ neu ) but has not been widely accepted in lung cancer therapy selection ([1][1

10.1158/1078-0432.ccr-06-0261

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Defining gefitinib sensitivity/resistance in non-small cell lung cancer (NSCLC) cell lines by affymetrix gene arrays

Journal of Clinical Oncology (2004)

Fred R. Hirsch Wilbur A. Franklin Samir E. Witta B. Helfrich Razvan Lapadat

7027 Background: Gefitinib (Iressa) and other EGFR inhibitors are active in 12–19% of NSCLC patients previously treated with chemotherapy. Currently, there are no selection criteria for determining which NSCLC patients will benefit from this treatment. EGFR expression does not predict Gefitinib sensitivity. Using a panel of NSCLC cell lines with varying sensitivity to Gefitinib we defined a panel of biomarkers that predict sensitivity or resistance. Methods: Gefitinib sensitivity was determined in 18 NSCLC cell lines using MTT assays. Cell lines were classified as Gefitinib sensitive (IC50<1μM), resistant (IC50>10μM) or intermediate sensitivity (IC50 1–10μM). Oligonucleotide microarray (Affymetrix HGU 133A, 22,000 genes) analysis was performed on 10 cell lines. Three distinct filtration and normalization algorithms were used to process the expression data and a list of genes was generated that was both statistically significant (unadjusted p=0.001 cutoff) and corrected for occurrence of false positives. This approach was used in combination with 5 distinct machine learning algorithms to build a test set for predictor genes that was successful in 100% of test cases. The best discriminators (>3 fold difference in expression between sensitive and resistant cell lines) were selected for quantitative real-time RT-PCR. Results: A list of 144 genes was generated from the Affymetric array analysis. By using the mathematical algorithm 16 candidate genes were selected for RT-PCR. Thirteen of the 16 genes were verified to discriminate between sensitive and resistant cell lines by quantitative real-time RT-PCR. Conclusions: Based on NSCLC cell line studies it was possible to identify 13 different genes, which strongly discriminated Gefitinib sensitive cell lines from the resistant ones. This biomarker panel may be of significant value for selecting NSCLC patients for Gefitinib treatment. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Amgen; AstraZeneca Allos Therapeutics; AstraZeneca Eli Lilly

10.1200/jco.2004.22.90140.7027

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Abstract 5439: Characterization of the class 1 histone deacetylase inhibitor entinostat in EGFRi acquired resistance models and in combination with cetuximab in NSCLC

Cancer Research (2010)

Daniel C. Chan Samir E. Witta Di Zheng Veronika Franekova Xiaomei Sui

Abstract Background: Entinostat is a novel oral benzamide HDACi characterized by its selectivity for class 1 HDACs as well as a unique pharmacokinetic (PK) and pharmacodynamic (PD) profile. Previous results have demonstrated the ability of entinostat to synergize in vitro and in vivo with the small molecule EGFR inhibitors, gefitinib and erlotinib as well as EGFR directed antibody, cetuximab to inhibit growth of EGFRi resistant NSCLC cells. The mechanism for the combined efficacy may involve a) targeting of EGFR gene and protein expression b) down-regulation of EGFR-mediated signal transduction pathway c) alteration of the tumor phenotype to re-sensitize cancer cells to EGFRi. Methods: The growth inhibitory effect of the combination of erlotinib and entinostat in H1975 and H1933 cells was determined using a 5-day 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. In vivo efficacy of entinostat was tested in athymic nude mice bearing NSCLC xenografts, A549 and H460. Combined treatment of entinostat with cetuximab was studied in H460 xenografts Results: We have extended our previous work examining the effect of entinostat on EGFRi resistance through testing of entinostat combined with erlotinib in cell line models of acquired resistance and evaluating the combination of entinostat with cetuximab in vivo in a xenograft model. Our results demonstrate that the combination of entinostat and erlotinib has enhanced activity in H1975 NSCLC cells which harbor the EGFRi T790M mutation. In addition the combination is more effective in H1933 NSCLC cells which have a met amplification. To further characterize the potential mechanism of action by which entinostat sensitizes NSCLC cells to EGFRi we have also tested entinostat in vivo in A549 and H460 xenograft models. Entinostat exhibits a dose response inhibition of tumor growth in both models and analysis of molecular markers is ongoing. In our previous experiments examining impact of entinostat on EGFRi resistance we reported on the combined efficacy of entinostat and cetuximab in the A549 NSCLC xenograft model. We have followed up on those initial findings through testing in a second xenograft model (H460) and will report those results. Conclusions: Entinostat enhances the effect of EGFR inhibitors in models of acquired EGFR resistance. The results from these experiments support the rationale of combining HDACi and EGFRi (small molecules as well as antibodies) in clinical studies in NSCLC. Ongoing clinical trials testing these hypothesis include ENCORE-401, a randomized, placebo controlled phase 2 study of erlotinib +/− entinostat in NSCLC patients and a pilot study, ENCORE-403 which was initiated to test the effect of entinostat on resistance to the EGFRi erlotinib in NSCLC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5439.

EGFR Inhibitors

Histone deacetylase inhibitor

Erlotinib Hydrochloride

T790M

10.1158/1538-7445.am10-5439

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Randomized Phase II Trial of Erlotinib With and Without Entinostat in Patients With Advanced Non–Small-Cell Lung Cancer Who Progressed on Prior Chemotherapy

Journal of Clinical Oncology (2012)

Samir E. Witta Robert M. Jotte Katrik Konduri Marcus A. Neubauer Alexander I. Spira

Histone deacetylase inhibitors (HDACis) have been shown to overcome resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) linked to epigenetic changes and epithelial-mesenchymal transition (EMT) state. This randomized phase II study evaluated the outcome of erlotinib with and without the isoform selective HDACi, entinostat.Previously treated patients with stage IIIB/IV non-small-cell lung cancer, no prior EGFR-TKIs, and performance status ≤ 2 were randomly administered erlotinib 150 mg on days 1 through 28 plus entinostat 10 mg orally on days 1 and 15 every 28 days (EE) or erlotinib plus placebo (EP). The primary end point was 4-month progression-free survival (PFS) rate with additional end points including 6-month PFS rate, PFS, and overall survival (OS). Exploratory analyses included EMT- and EGFR-related biomarker analysis on archival tissue.One hundred thirty-two patients were enrolled (EE, 67; EP, 65). The 4-month PFS rate was comparable for both groups (EE, 18% v EP, 20%; P = .7). In the subset of patients with high E-cadherin levels, OS was longer in the EE group compared with the EP group (9.4 v 5.4 months; hazard ratio, 0.35; 95% CI, 0.13 to 0.92; P = .03) with a corresponding trend toward increased PFS. The adverse event (AE) profile was acceptable, with rash, fatigue, diarrhea, and nausea the most common AEs in both groups.Erlotinib combined with entinostat did not improve the outcomes of patients in the overall study population when compared with erlotinib monotherapy. High E-cadherin expression levels at time of diagnosis indicate an increased sensitivity to HDACi/EGFR-TKI inhibition providing the basis for a biomarker-driven validation study.

Clinical endpoint

10.1200/jco.2011.38.9411

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Citations (185)

Baseline Gene Expression Predicts Sensitivity to Gefitinib in Non–Small Cell Lung Cancer Cell Lines

Molecular Cancer Research (2006)

Christopher D. Coldren Barbara A. Helfrich Samir E. Witta Michio Sugita Razvan Lapadat

Tyrosine kinase inhibitors (TKI) of the epidermal growth factor receptor (EGFR) produce objective responses in a minority of patients with advanced-stage non-small cell lung cancer (NSCLC), and about half of all treated patients progress within 6 weeks of instituting therapy. Because the target of these agents is known, it should be possible to develop biological predictors of response, but EGFR protein levels have not been proven useful as a predictor of TKI response in patients and the mechanism of primary resistance is unclear. We used microarray gene expression profiling to uncover a pattern of gene expression associated with sensitivity to EGFR-TKIs by comparing NSCLC cell lines that were either highly sensitive or highly resistant to gefitinib. This sensitivity-associated expression profile was used to predict gefitinib sensitivity in a panel of NSCLC cell lines with known gene expression profiles but unknown gefitinib sensitivity. Gefitinib sensitivity was then determined for members of this test panel, and the microarray-based sensitivity prediction was correct in eight of nine NSCLC cell lines. Gene and protein expression differences were confirmed with a combination of quantitative reverse transcription-PCR, flow cytometry, and immunohistochemistry. This gene expression pattern related to gefitinib sensitivity was independent from sensitivity associated with EGFR mutations. Several genes associated with sensitivity encode proteins involved in HER pathway signaling or pathways that interrelate to the HER signaling pathway. Some of these genes could be targets of pharmacologic interventions to overcome primary resistance.

10.1158/1541-7786.mcr-06-0095

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Citations (139)