218 results on '"Siegfried JM"'
Search Results
2. Inhibition of human non-small cell lung tumors by a c-Met antisense/U6 expression plasmid strategy
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Stabile, LP, Lyker, JS, Huang, L, and Siegfried, JM
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- 2004
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3. HGF-independent potentiation of EGFR action by c-Met
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Dulak, AM, Gubish, CT, Stabile, LP, Henry, C, and Siegfried, JM
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- 2011
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4. Functional analyses of ATM, ATR and Fanconi anemia proteins in lung carcinoma
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Beumer, JH, Fu, KY, Anyang, BN, Siegfried, JM, Bakkenist, CJ, Beumer, JH, Fu, KY, Anyang, BN, Siegfried, JM, and Bakkenist, CJ
- Abstract
Background: ATM and ATR are kinases implicated in a myriad of DNA-damage responses. ATM kinase inhibition radiosensitizes cells and selectively kills cells with Fanconi anemia (FA) gene mutations. ATR kinase inhibition sensitizes cells to agents that induce replication stress and selectively kills cells with ATM and TP53 mutations. ATM mutations and FANCF promoter-methylation are reported in lung carcinomas. Methods: We undertook functional analyses of ATM, ATR, Chk1 and FA proteins in lung cancer cell lines. We included Calu6 that is reported to be FANCL-deficient. In addition, the cancer genome atlas (TCGA) database was interrogated for alterations in: 1) ATM, MRE11A, RAD50 and NBN; 2) ATR, ATRIP and TOPBP1; and 3) 15 FA genes. Results: No defects in ATM, ATR or Chk1 kinase activation, or FANCD2 monoubiquitination were identified in the lung cancer cell lines examined, including Calu6, and major alterations in these pathways were not identified in the TCGA database. Cell lines were radiosensitized by ATM kinase inhibitor KU60019, but no cell killing by ATM kinase inhibitor alone was observed. While no synergy between gemcitabine or carboplatin and ATR kinase inhibitor ETP-46464 was observed, synergy between gemcitabine and Chk1 kinase inhibitor UCN-01 was observed in 54T, 201T and H460, and synergy between carboplatin and Chk1 kinase inhibitor was identified in 201T and 239T. No interactions between ATM, ATR and FA activation were observed by either ATM or ATR kinase inhibition in the lung cancer cell lines. Conclusions: Analyses of ATM serine 1981 and Chk1 serine 345 phosphorylation, and FANCD2 monoubiquitination revealed that ATM and ATR kinase activation and FA pathway signaling are intact in the lung cancer cell lines examined. As such, these posttranslational modifications may have utility as biomarkers for the integrity of DNA damage signaling pathways in lung cancer. Different sensitization profiles between gemcitabine and carboplatin and ATR kinase inhibit
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- 2015
5. Validation of a blood protein signature for non-small cell lung cancer
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Mehan, MR, Williams, SA, Siegfried, JM, Bigbee, WL, Weissfeld, JL, Wilson, DO, Pass, HI, Rom, WN, Muley, T, Meister, M, Franklin, W, Miller, YE, Brody, EN, Ostroff, RM, Mehan, MR, Williams, SA, Siegfried, JM, Bigbee, WL, Weissfeld, JL, Wilson, DO, Pass, HI, Rom, WN, Muley, T, Meister, M, Franklin, W, Miller, YE, Brody, EN, and Ostroff, RM
- Abstract
Background: CT screening for lung cancer is effective in reducing mortality, but there are areas of concern, including a positive predictive value of 4% and development of interval cancers. A blood test that could manage these limitations would be useful, but development of such tests has been impaired by variations in blood collection that may lead to poor reproducibility across populations. Results: Blood-based proteomic profiles were generated with SOMAscan technology, which measured 1033 proteins. First, preanalytic variability was evaluated with Sample Mapping Vectors (SMV), which are panels of proteins that detect confounders in protein levels related to sample collection. A subset of well collected serum samples not influenced by preanalytic variability was selected for discovery of lung cancer biomarkers. The impact of sample collection variation on these candidate markers was tested in the subset of samples with higher SMV scores so that the most robust markers could be used to create disease classifiers. The discovery sample set (n = 363) was from a multi-center study of 94 non-small cell lung cancer (NSCLC) cases and 269 long-term smokers and benign pulmonary nodule controls. The analysis resulted in a 7-marker panel with an AUC of 0.85 for all cases (68% adenocarcinoma, 32% squamous) and an AUC of 0.93 for squamous cell carcinoma in particular. This panel was validated by making blinded predictions in two independent cohorts (n = 138 in the first validation and n = 135 in the second). The model was recalibrated for a panel format prior to unblinding the second cohort. The AUCs overall were 0.81 and 0.77, and for squamous cell tumors alone were 0.89 and 0.87. The estimated negative predictive value for a 15% disease prevalence was 93% overall and 99% for squamous lung tumors. The proteins in the classifier function in destruction of the extracellular matrix, metabolic homeostasis and inflammation. Conclusions: Selecting biomarkers resistant to sample proc
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- 2014
6. Gastrin-releasing peptide receptor expression in non-cancerous bronchial epithelia is associated with lung cancer: A case-control study
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Egloff, AM, Gaither Davis, A, Shuai, Y, Land, S, Pilewski, JM, Luketich, JD, Landreneau, R, Miller, YE, Grandis, JR, Siegfried, JM, Egloff, AM, Gaither Davis, A, Shuai, Y, Land, S, Pilewski, JM, Luketich, JD, Landreneau, R, Miller, YE, Grandis, JR, and Siegfried, JM
- Abstract
Background: Normal bronchial tissue expression of GRPR, which encodes the gastrin-releasing peptide receptor, has been previously reported by us to be associated with lung cancer risk in 78 subjects, especially in females. We sought to define the contribution of GRPR expression in bronchial epithelia to lung cancer risk in a larger case-control study where adjustments could be made for tobacco exposure and sex.Methods: We evaluated GRPR mRNA levels in histologically normal bronchial epithelial cells from 224 lung cancer patients and 107 surgical cancer-free controls. Associations with lung cancer were tested using logistic regression models.Results: Bronchial GRPR expression was significantly associated with lung cancer (OR = 4.76; 95% CI = 2.32-9.77) in a multivariable logistic regression (MLR) model adjusted for age, sex, smoking status and pulmonary function. MLR analysis stratified by smoking status indicated that ORs were higher in never and former smokers (OR = 7.74; 95% CI = 2.96-20.25) compared to active smokers (OR = 1.69; 95% CI = 0.46-6.33). GRPR expression did not differ by subject sex, and lung cancer risk associated with GRPR expression was not modified by sex.Conclusions: GRPR expression in non-cancerous bronchial epithelium was significantly associated with the presence of lung cancer in never and former smokers. The association in never and former smokers was found in males and females. Association with lung cancer did not differ by sex in any smoking group. © 2012 Egloff et al; licensee BioMed Central Ltd.
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- 2012
7. Unlocking biomarker discovery: Large scale application of aptamer proteomic technology for early detection of lung cancer
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Ostroff, RM, Bigbee, WL, Franklin, W, Gold, L, Mehan, M, Miller, YE, Pass, HI, Rom, WN, Siegfried, JM, Stewart, A, Walker, JJ, Weissfeld, JL, Williams, S, Zichi, D, Brody, EN, Ostroff, RM, Bigbee, WL, Franklin, W, Gold, L, Mehan, M, Miller, YE, Pass, HI, Rom, WN, Siegfried, JM, Stewart, A, Walker, JJ, Weissfeld, JL, Williams, S, Zichi, D, and Brody, EN
- Abstract
Background: Lung cancer is the leading cause of cancer deaths worldwide. New diagnostics are needed to detect early stage lung cancer because it may be cured with surgery. However, most cases are diagnosed too late for curative surgery. Here we present a comprehensive clinical biomarker study of lung cancer and the first large-scale clinical application of a new aptamer-based proteomic technology to discover blood protein biomarkers in disease. Methodology/Principal Findings: We conducted a multi-center case-control study in archived serum samples from 1,326 subjects from four independent studies of non-small cell lung cancer (NSCLC) in long-term tobacco-exposed populations. Sera were collected and processed under uniform protocols. Case sera were collected from 291 patients within 8 weeks of the first biopsy-proven lung cancer and prior to tumor removal by surgery. Control sera were collected from 1,035 asymptomatic study participants with ≥10 pack-years of cigarette smoking. We measured 813 proteins in each sample with a new aptamer-based proteomic technology, identified 44 candidate biomarkers, and developed a 12-protein panel (cadherin-1, CD30 ligand, endostatin, HSP90a, LRIG3, MIP-4, pleiotrophin, PRKCI, RGM-C, SCF-sR, sL-selectin, and YES) that discriminates NSCLC from controls with 91% sensitivity and 84% specificity in cross-validated training and 89% sensitivity and 83% specificity in a separate verification set, with similar performance for early and late stage NSCLC. Conclusions/Significance: This study is a significant advance in clinical proteomics in an area of high unmet clinical need. Our analysis exceeds the breadth and dynamic range of proteome interrogated of previously published clinical studies of broad serum proteome profiling platforms including mass spectrometry, antibody arrays, and autoantibody arrays. The sensitivity and specificity of our 12-biomarker panel improves upon published protein and gene expression panels. Separate verification
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- 2010
8. A multiplexed serum biomarker immunoassay panel discriminates clinical lung cancer patients from high-risk individuals found to be cancer-free by CT screening.
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Bigbee WL, Gopalakrishnan V, Weissfeld JL, Wilson DO, Dacic S, Lokshin AE, Siegfried JM, Bigbee, William L, Gopalakrishnan, Vanathi, Weissfeld, Joel L, Wilson, David O, Dacic, Sanja, Lokshin, Anna E, and Siegfried, Jill M
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- 2012
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9. Combining the multitargeted tyrosine kinase inhibitor vandetanib with the antiestrogen fulvestrant enhances its antitumor effect in non-small cell lung cancer.
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Siegfried JM, Gubish CT, Rothstein ME, Henry C, Stabile LP, Siegfried, Jill M, Gubish, Christopher T, Rothstein, Mary E, Henry, Cassandra, and Stabile, Laura P
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- 2012
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10. Doubling times and CT screen–detected lung cancers in the Pittsburgh Lung Screening Study.
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Wilson DO, Ryan A, Fuhrman C, Schuchert M, Shapiro S, Siegfried JM, Weissfeld J, Wilson, David O, Ryan, Adam, Fuhrman, Carl, Schuchert, Matthew, Shapiro, Steven, Siegfried, Jill M, and Weissfeld, Joel
- Abstract
Rationale: As computed tomography (CT) screening for lung cancer becomes more widespread, volumetric analyses, including doubling times, of CT-screen detected lung nodules and lung cancers may provide useful information in the follow-up and management of CT-detected lung nodules and cancers.Objectives: To analyze doubling times in CT screen detected lung cancers and compare prevalent and nonprevalent cancers and different cell types on non small cell lung cancer.Methods: We performed volumetric and doubling time analysis on 63 non–small cell lung cancers detected as part of the Pittsburgh Lung Screening Study using a commercially available VITREA 2 workstation and VITREA VITAL nodule segmentation software.Measurements and Main Results: Doubling times (DT) were divided into three groups: rapid (DT<183 d), typical (DT 183–365 d), and slow (DT>365 d). Adenocarcinoma/bronchioloalveolar carcinoma comprised 86.7% of the slow DT group compared with 20% of the rapid DT group. Conversely, squamous cell cancer comprised 60% of the rapid DT group compared with 3.3% of the slow DT group. Twenty-eight of 42 (67%) prevalent and 2 of 21 (10%) nonprevalent cancers were in the slow DT group (P<0.0001; Fisher's exact test). Twenty-four of 32 (75%) prevalent and 1 of 11 (9%) nonprevalent adenocarcinomas were in the slow DT group (P<0.0002; Fisher's exact test).Conclusions: Volumetric analysis of CT-detected lung cancers is particularly useful in AC/BAC. Prevalent cancers have a significantly slower DT than nonprevalent cancers and a higher percentage of adenocarcinoma/bronchioloalveolar carcinoma. These results should affect the management of indeterminant lung nodules detected on screening CT scans. [ABSTRACT FROM AUTHOR]- Published
- 2012
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11. Lung cancer serum biomarker discovery using label-free liquid chromatography-tandem mass spectrometry.
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Zeng X, Hood BL, Zhao T, Conrads TP, Sun M, Gopalakrishnan V, Grover H, Day RS, Weissfeld JL, Wilson DO, Siegfried JM, Bigbee WL, Zeng, Xuemei, Hood, Brian L, Zhao, Ting, Conrads, Thomas P, Sun, Mai, Gopalakrishnan, Vanathi, Grover, Himanshu, and Day, Roger S
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- 2011
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12. The Pittsburgh Lung Screening Study (PLuSS): outcomes within 3 years of a first computed tomography scan.
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Wilson DO, Weissfeld JL, Fuhrman CR, Fisher SN, Balogh P, Landreneau RJ, Luketich JD, Siegfried JM, Wilson, David O, Weissfeld, Joel L, Fuhrman, Carl R, Fisher, Stephen N, Balogh, Paula, Landreneau, Rodney J, Luketich, James D, and Siegfried, Jill M
- Abstract
Rationale: The role of computed tomography (CT) screening for lung cancer is controversial, currently under study, and not yet fully elucidated.Objectives: To report findings from initial and 1-year repeat screening low-radiation-dose CT of the chest and 3-year outcomes for 50- to 79-year-old current and ex-smokers in the Pittsburgh Lung Screening Study (PLuSS).Methods: Notified of findings on screening CT, subjects received diagnostic advice from both study and personal physicians. Tracking subjects for up to three years since initial screening, we obtained medical records to document diagnostic procedures, lung cancer diagnoses, and deaths.Measurements and Main Results: 3,642 and 3,423 subjects had initial and repeat screening. A total of 1,477 (40.6% of 3,624) were told about noncalcified lung nodules on the initial screening and, before repeat screening, 821 (55.6% of 1,477, 22.5% of 3,642) obtained one or more subsequent diagnostic imaging studies (CT, positron emission tomography [PET], or PET-CT). Tracking identified 80 subjects with lung cancer, including 53 subjects with tumor seen at initial screening. In all, 36 subjects (1.0% of the 3,642 screened), referred for abnormalities on either the initial or repeat screening, had a major thoracic surgical procedure (thoracotomy, video-assisted thoracoscopic surgery [VATS], median sternotomy, or mediastinoscopy) leading to a noncancer final diagnosis. Out of 82 subjects with thoracotomy or VATS to exclude malignancy in a lung nodule, 28 (34.1%) received a noncancer final diagnosis. Forty of 69 (58%) subjects with non-small cell lung cancer had stage I disease at diagnosis.Conclusions: Though leading to the discovery of early stage lung cancer, CT screening also led to many diagnostic follow-up procedures, including major thoracic surgical procedures with noncancer outcomes. [ABSTRACT FROM AUTHOR]- Published
- 2008
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13. Association of radiographic emphysema and airflow obstruction with lung cancer.
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Wilson DO, Weissfeld JL, Balkan A, Schragin JG, Fuhrman CR, Fisher SN, Wilson J, Leader JK, Siegfried JM, Shapiro SD, Sciurba FC, Wilson, David O, Weissfeld, Joel L, Balkan, Arzu, Schragin, Jeffrey G, Fuhrman, Carl R, Fisher, Stephen N, Wilson, Jonathan, Leader, Joseph K, and Siegfried, Jill M
- Abstract
Rationale: To study the relationship between emphysema and/or airflow obstruction and lung cancer in a high-risk population.Objective: We studied lung cancer related to radiographic emphysema and spirometric airflow obstruction in tobacco-exposed persons who were screened for lung cancer using chest computed tomography (CT).Methods: Subjects completed questionnaires, spirometry, and low-dose helical chest CT. CT scans were scored for emphysema based on National Emphysema Treatment Trial criteria. Multiple logistic regressions estimated the independent associations between various factors, including radiographic emphysema and airflow obstruction, and subsequent lung cancer diagnosis.Measurements and Main Results: Among 3,638 subjects, 57.5, 18.8, 14.6, and 9.1% had no, trace, mild, and moderate-severe emphysema, and 57.3, 13.6, 22.8, and 6.4% had no, mild (Global Initiative for Chronic Obstructive Lung Disease [GOLD] I), moderate (GOLD II), and severe (GOLD III-IV) airflow obstruction. Of 3,638 subjects, 99 (2.7%) received a lung cancer diagnosis. Adjusting for sex, age, years of cigarette smoking, and number of cigarettes smoked daily, logistic regression showed the expected lung cancer association with the presence of airflow obstruction (GOLD I-IV, odds ratio [OR], 2.09; 95% confidence interval [CI], 1.33-3.27). A second logistic regression showed lung cancer related to emphysema (OR, 3.56; 95% CI, 2.21-5.73). After additional adjustments for GOLD class, emphysema remained a strong and statistically significant factor related to lung cancer (OR, 3.14; 95% CI, 1.91-5.15).Conclusions: Emphysema on CT scan and airflow obstruction on spirometry are related to lung cancer in a high-risk population. Emphysema is independently related to lung cancer. Both radiographic emphysema and airflow obstruction should be considered when assessing lung cancer risk. [ABSTRACT FROM AUTHOR]- Published
- 2008
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14. Non-small-cell lung cancer and breast carcinoma: chemotherapy and beyond.
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Dubey S, Siegfried JM, and Traynor AM
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Early screening, adjuvant and sequential systemic treatment, and hormonal therapy have benefits in treatment of breast cancer. Management of non-small-cell lung cancer (NSCLC) is progressing and will hopefully follow in the same footsteps as that of breast cancer. Only recently have clinical trials established adjuvant treatment as the standard of care in lung cancer. A growing number of effective cytotoxic and targeted agents have resulted in increased survival when used as sequential treatment in both breast cancer and NSCLC. The interaction between oestrogen receptors (ER) in the lung and epidermal growth factor receptor (EGFR) suggests a potential role for endocrine manipulation in the treatment of NSCLC. This complex interaction involves several types of ER receptors and different signalling pathways. Interactions between tobacco and oestrogen confound the effects of exogenous oestrogens on risk of lung cancer, but not on that of breast cancer. The optimum application of hormonal manipulation to prevent or treat lung cancer will depend on a more-complete understanding of lung-specific ER signalling. Early trials have assessed the interaction between the ER and EGFR signalling. [ABSTRACT FROM AUTHOR]
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- 2006
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15. The American Cancer Society National Lung Cancer Roundtable strategic plan: Lung cancer in women.
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Backhus LM, Chang CF, Sakoda LC, Chambers SR, Henderson LM, Henschke CI, Hollenbeck GJ, Jacobson FL, Martin LW, Proctor ED, Schiller JH, Siegfried JM, Wisnivesky JP, Wolf AS, Jemal A, Kelly K, Sandler KL, Watkins PN, Smith RA, and Rivera MP
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Lung cancer in women is a modern epidemic and represents a global health crisis. Cigarette smoking remains the most important risk factor for lung cancer in all patients and, among women globally, rates of smoking continue to increase. Although some data exist supporting sex-based differences across the continuum of lung cancer, there is currently a dearth of research exploring the differences in risk, biology, and treatment outcomes in women. Consequently, the American Cancer Society National Lung Cancer Roundtable recognizes the urgent need to promote awareness and future research that will close the knowledge gaps regarding lung cancer in women. To this end, the American Cancer Society National Lung Cancer Roundtable Task Group on Lung Cancer in Women convened a summit undertaking the following to: (1) summarize existing evidence and identify knowledge gaps surrounding the epidemiology, risk factors, biologic differences, and outcomes of lung cancer in women; (2) develop and prioritize research topics and questions that address research gaps and advance knowledge to improve quality of care of lung cancer in women; and (3) propose strategies for future research. PLAIN LANGUAGE SUMMARY: Lung cancer is the leading cause of cancer mortality in women, and, despite comparatively lower exposures to occupational and environmental carcinogens compared with men, disproportionately higher lung cancer rates in women who ever smoked and women who never smoked call for increased awareness and research that will close the knowledge gaps regarding lung cancer in women., (© 2024 The Author(s). Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)
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- 2024
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16. Early natural menopause is associated with poor lung health and increased mortality among female smokers.
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Zhai T, Diergaarde B, Wilson DO, Kang H, Sood A, Bayliss SH, Yuan JM, Picchi MA, Lan Q, Belinsky SA, Siegfried JM, Cook LS, and Leng S
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- Aged, Female, Humans, Middle Aged, Forced Expiratory Volume, Lung, Menopause, Smokers, Lung Neoplasms, Menopause, Premature
- Abstract
Background: Early natural menopause has been regarded as a biomarker of reproductive and somatic aging. Cigarette smoking is the most harmful factor for lung health and also an established risk factor for early menopause. Understanding the effect of early menopause on health outcomes in middle-aged and older female smokers is important to develop preventive strategies., Objective: This study aimed to examine the associations of early menopause with multiple lung health and aging biomarkers, lung cancer risk, and all-cause and cause-specific mortality in postmenopausal women who were moderate or heavy smokers., Study Design: This study was conducted on postmenopausal women with natural (n=1038) or surgical (n=628) menopause from the Pittsburgh Lung Screening Study. The Pittsburgh Lung Screening Study is a community-based research cohort of current and former smokers, screened with low-dose computed tomography and followed up for lung cancer. Early menopause was defined as occurring before 45 years of age. The analyses were stratified by menopause types because of the different biological and medical causes of natural and surgical menopause. Statistical methods included linear model, generalized linear model, linear mixed-effects model, and time-to-event analysis., Results: The average age of the 1666 female smokers was 59.4±6.7 years, with 1519 (91.2%) of the population as non-Hispanic Whites and 1064 (63.9%) of the population as current smokers at baseline. Overall, 646 (39%) women reported early menopause, including 198 (19.1%) women with natural menopause and 448 (71.3%) women with surgical menopause (P<.001). Demographic variables did not differ between early and nonearly menopause groups, regardless of menopause type. Significant associations were identified between early natural menopause and higher risk of wheezing (odds ratio, 1.65; P<.01), chronic bronchitis (odds ratio, 1.73; P<.01), and radiographic emphysema (odds ratio, 1.70; P<.001) and lower baseline lung spirometry in an obstructive pattern (-104.8 mL/s for forced expiratory volume in the first second with P<.01, -78.6 mL for forced vital capacity with P=.04, and -2.1% for forced expiratory volume in the first second-to-forced vital capacity ratio with P=.01). In addition, early natural menopause was associated with a more rapid decline of forced expiratory volume in the first second-to-forced vital capacity ratio (-0.16% per year; P=.01) and incident airway obstruction (odds ratio, 2.02; P=.04). Furthermore, women early natural menopause had a 40% increased risk of death (P=.023), which was mainly driven by respiratory diseases (hazard ratio, 2.32; P<.001). Mediation analyses further identified that more than 33.3% of the magnitude of the associations between early natural menopause and all-cause and respiratory mortality were explained by baseline forced expiratory volume in the first second. Additional analyses in women with natural menopause identified that the associations between continuous smoking and subsequent lung cancer risk and cancer mortality were moderated by early menopause status, and females with early natural menopause who continued smoking had the worst outcomes (hazard ratio, >4.6; P<.001). This study did not find associations reported above in female smokers with surgical menopause., Conclusion: Early natural menopause was found to be a risk factor for malignant and nonmalignant lung diseases and mortality in middle-aged and older female smokers. These findings have strong public health relevance as preventive strategies, including smoking cessation and chest computed tomography screening, should target this population (ie, female smokers with early natural menopause) to improve their postmenopausal health and well-being., (Copyright © 2022 Elsevier Inc. All rights reserved.)
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- 2022
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17. Sex and Gender Differences in Lung Cancer and Chronic Obstructive Lung Disease.
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Siegfried JM
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- Age Factors, Animals, Estrogen Replacement Therapy, Estrogens physiology, Female, Humans, Immune System, Lung Neoplasms genetics, Lung Neoplasms pathology, Male, Middle Aged, Prognosis, Pulmonary Disease, Chronic Obstructive genetics, Pulmonary Disease, Chronic Obstructive pathology, Smoking epidemiology, Lung Neoplasms epidemiology, Pulmonary Disease, Chronic Obstructive epidemiology, Sex Characteristics, Sex Factors
- Abstract
Two highly prevalent pulmonary diseases, lung cancer and chronic obstructive lung disease (COPD), show both sex and gender differences in their presentations and outcomes. Sex differences are defined as biological differences associated with the male vs female genotype, and gender differences are defined as behavioral or social differences that primarily arise because of gender identity. The incidence of both lung cancer and COPD has increased dramatically in women over the past 50 years, and both are associated with chronic pulmonary inflammation. Development of COPD is also a risk factor for lung cancer. In this review, the main differences in lung cancer and COPD biology observed between men and women will be summarized. Potential causative factors will be discussed, including the role of estrogen in promoting pro-growth and inflammatory phenotypes which may contribute to development of both lung cancer and COPD. Response of the innate and adaptive immune system to estrogen is a likely factor in the biology of both lung cancer and COPD. Estrogen available from synthesis by reproductive organs as well as local pulmonary estrogen synthesis may be involved in activating estrogen receptors expressed by multiple cell types in the lung. Estrogenic actions, although more pronounced in women, may also have importance in the biology of lung cancer and COPD in men. Effects of estrogen are also timing and context dependent; the multiple cell types that mediate estrogen action in the lungs may confer both positive and negative effects on disease processes., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
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- 2022
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18. Targeting the ERβ/HER Oncogenic Network in KRAS Mutant Lung Cancer Modulates the Tumor Microenvironment and Is Synergistic with Sequential Immunotherapy.
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Almotlak AA, Farooqui M, Soloff AC, Siegfried JM, and Stabile LP
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- Animals, CD8-Positive T-Lymphocytes drug effects, CD8-Positive T-Lymphocytes immunology, Carcinogenesis genetics, Carcinogenesis immunology, Cell Line, Tumor, Estrogen Receptor beta immunology, Female, Humans, Immunotherapy methods, Lung Neoplasms immunology, Lung Neoplasms therapy, Lymphocytes, Tumor-Infiltrating drug effects, Lymphocytes, Tumor-Infiltrating immunology, Macrophages drug effects, Macrophages immunology, Mice, Oncogenes genetics, Oncogenes immunology, Programmed Cell Death 1 Receptor genetics, Proto-Oncogene Proteins p21(ras) immunology, Quinazolinones pharmacology, Receptor, ErbB-2 immunology, Tumor Microenvironment immunology, Estrogen Receptor beta genetics, Lung Neoplasms genetics, Proto-Oncogene Proteins p21(ras) genetics, Receptor, ErbB-2 genetics, Tumor Microenvironment genetics
- Abstract
High ERβ/HER oncogenic signaling defines lung tumors with an aggressive biology. We previously showed that combining the anti-estrogen fulvestrant with the pan-HER inhibitor dacomitinib reduced ER/HER crosstalk and produced synergistic anti-tumor effects in immunocompromised lung cancer models, including KRAS mutant adenocarcinoma. How this combination affects the tumor microenvironment (TME) is not known. We evaluated the effects of fulvestrant and dacomitinib on murine bone marrow-derived macrophages (BMDMs) and CD8+ T cells, and tested the efficacy of the combination in vivo, using the KRAS mutant syngeneic lung adenocarcinoma model, FVBW-17. While this combination synergistically inhibited proliferation of FVBW-17 cells, it had unwanted effects on immune cells, by reducing CD8+ T cell activity and phagocytosis in BMDMs and inducing PD-1. The effects were largely attributed to dacomitinib, which caused downregulation of Src family kinases and Syk in immune cells. In a subcutaneous flank model, the combination induced an inflamed TME with increased myeloid cells and CD8+ T cells and enhanced PD-1 expression in the splenic compartment. Concomitant administration of anti-PD-1 antibody with fulvestrant and dacomitinib was more efficacious than fulvestrant plus dacomitinib alone. Administering anti-PD-1 sequentially after fulvestrant plus dacomitinib was synergistic, with a two-fold greater tumor inhibitory effect compared to concomitant therapy, in both the flank model and in a lung metastasis model. Sequential triple therapy has potential for treating lung cancer that shows limited response to current therapies, such as KRAS mutant lung adenocarcinoma.
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- 2021
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19. Meeting Report: Translational Advances in Cancer Prevention Agent Development Meeting.
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Miller MS, Allen PJ, Brown PH, Chan AT, Clapper ML, Dashwood RH, Demehri S, Disis ML, DuBois RN, Glynn RJ, Kensler TW, Khan SA, Johnson BD, Liby KT, Lipkin SM, Mallery SR, Meuillet EJ, Roden RBS, Schoen RE, Sharp ZD, Shirwan H, Siegfried JM, Rao CV, You M, Vilar E, Szabo E, and Mohammed A
- Abstract
The Division of Cancer Prevention of the National Cancer Institute (NCI) and the Office of Disease Prevention of the National Institutes of Health co-sponsored the Translational Advances in Cancer Prevention Agent Development Meeting on August 27 to 28, 2020. The goals of this meeting were to foster the exchange of ideas and stimulate new collaborative interactions among leading cancer prevention researchers from basic and clinical research; highlight new and emerging trends in immunoprevention and chemoprevention as well as new information from clinical trials; and provide information to the extramural research community on the significant resources available from the NCI to promote prevention agent development and rapid translation to clinical trials. The meeting included two plenary talks and five sessions covering the range from pre-clinical studies with chemo/immunopreventive agents to ongoing cancer prevention clinical trials. In addition, two NCI informational sessions describing contract resources for the preclinical agent development and cooperative grants for the Cancer Prevention Clinical Trials Network were also presented., Competing Interests: CONFLICTS OF INTEREST Drs. Allen, Clapper, Dashwood, Demehri, DuBois, Johnson, Kensler, Khan, Mallery, Miller, Mohammed, Rao, Schoen, Sharp, Szabo, and You have no FCOI to declare. Dr. Brown owns stock in GeneTex, whose products are not discussed in this manuscript. Dr. Chan has previously received grant support and consulting fees from Bayer Pharma AG; consulting fees from Pfizer Inc. and Boehringer Ingelheim. Dr. Disis received grant funding from Pfizer, Precigen, Bavarian Nordisk, and Veanna; is a stockholder in Epithany; and is an inventor with patents held by the University of Washington. Dr. Glynn has received support from research grants to his employer from AstraZeneca, Kowa, and Pfizer. The Brigham & Women’s Hospital holds patents for use of inflammatory biomarkers in cardiovascular disease. The CANTOS trial was funded by Novartis. Dr. Liby is an inventor on patents for synthetic triterpenoids and rexinoids. Dr. Lipkin is PI on grant U01-CA233056 that includes work performed by Nouscom, LLC. Dr. Meuillet is a scientific co-founder and member of the Management Team of PHusis, which is developing PHT-427. Dr. Roden is a co-founder of and has an equity ownership interest in Papivax LLC. Also, he owns Papivax Biotech Inc. stock options and is a member of Papivax Biotech Inc.’s Scientific Advisory Board. Under a licensing agreement between Papivax Biotech, Inc. and the Johns Hopkins University, the University and Dr. Roden are entitled to royalties on an invention described in this article. This arrangement has been reviewed and approved by the Johns Hopkins University in accordance with its conflict of interest policies. Dr. Siegfried has a US Patent Pending: #62650892. Dr. Shirwan is a CEO at FasCure Therapeutics, LLC, and has ownership interest (including stocks and patents) in the Company. Dr. Vilar has a consulting or advisory role with Janssen Research and Development, and Recursion Pharma., (Copyright © 2021 Korean Society of Cancer Prevention.)
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- 2021
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20. Anti-EGFR Fibronectin Bispecific Chemically Self-Assembling Nanorings (CSANs) Induce Potent T Cell-Mediated Antitumor Responses and Downregulation of EGFR Signaling and PD-1/PD-L1 Expression.
- Author
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Kilic O, Matos de Souza MR, Almotlak AA, Wang Y, Siegfried JM, Distefano MD, and Wagner CR
- Subjects
- Animals, Antibodies, Bispecific immunology, B7-H1 Antigen antagonists & inhibitors, CD3 Complex immunology, Cell Line, Tumor, Down-Regulation, ErbB Receptors immunology, ErbB Receptors metabolism, Female, Fibronectins immunology, Humans, Immune Checkpoint Inhibitors immunology, Mice, Inbred NOD, Mice, SCID, Programmed Cell Death 1 Receptor metabolism, Signal Transduction drug effects, Single-Chain Antibodies immunology, Antibodies, Bispecific therapeutic use, Fibronectins therapeutic use, Immune Checkpoint Inhibitors therapeutic use, Neoplasms therapy, Single-Chain Antibodies therapeutic use, T-Lymphocytes metabolism
- Abstract
Overexpression of the epidermal growth factor receptor (EGFR) on various cancers makes it an important target for cancer immunotherapy. We recently demonstrated that single-chain variable fragment-based bispecific chemically self-assembled nanorings (CSANs) can successfully modify T cell surfaces and function as prosthetic antigen receptors (PARs) allowing selective targeting of tumor antigens while incorporating a dissociation mechanism of the rings. Here, we report the generation of anti-EGFR fibronectin (FN3)-based PARs with high yield, rapid protein production, predicted low immunogenicity, and increased protein stability. We demonstrated the cytotoxicity of FN3-PARs successfully while evaluating FN3 affinities, CSAN valencies, and antigen expression levels. Using an orthotopic breast cancer model, we showed that FN3-PARs can suppress tumor growth with no adverse effects and FN3-PARs reduced immunosuppressive programmed cell death ligand-1 (PD-L1) expression by downregulating EGFR signaling. These results demonstrate the potential of FN3-PARs to direct selective T cell-targeted tumor killing and to enhance antitumor T cell efficacy by modulating the tumor microenvironment.
- Published
- 2020
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21. Prevention of Tobacco Carcinogen-Induced Lung Tumor Development by a Novel STAT3 Decoy Inhibitor.
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Njatcha C, Farooqui M, Almotlak AA, and Siegfried JM
- Subjects
- Animals, Anticarcinogenic Agents therapeutic use, Butanones toxicity, Carcinogenesis chemically induced, Carcinogenesis drug effects, Carcinogens toxicity, Carcinoma, Non-Small-Cell Lung chemically induced, Carcinoma, Non-Small-Cell Lung genetics, Carcinoma, Non-Small-Cell Lung immunology, Cell Proliferation drug effects, Gene Expression Regulation, Neoplastic drug effects, Humans, Lung drug effects, Lung pathology, Lung Neoplasms chemically induced, Lung Neoplasms genetics, Lung Neoplasms immunology, Mice, Mutation, Neoplasms, Experimental chemically induced, Neoplasms, Experimental genetics, Neoplasms, Experimental pathology, Neoplasms, Experimental prevention & control, Nitrosamines toxicity, Oligonucleotides pharmacology, Oligonucleotides therapeutic use, Proto-Oncogene Proteins p21(ras) genetics, STAT3 Transcription Factor genetics, STAT3 Transcription Factor metabolism, Signal Transduction drug effects, Nicotiana chemistry, Transcriptional Activation drug effects, Tumor Microenvironment drug effects, Tumor Microenvironment immunology, Anticarcinogenic Agents pharmacology, Carcinoma, Non-Small-Cell Lung prevention & control, Lung Neoplasms prevention & control, STAT3 Transcription Factor antagonists & inhibitors, Nicotiana toxicity
- Abstract
The STAT3 pathway is frequently overactive in non-small cell lung cancer (NSCLC), an often fatal disease with known risk factors including tobacco and chemical exposures. Whether STAT3 can be downmodulated to delay or prevent development of lung cancer resulting from an environmental exposure has not been previously tested. A circular oligonucleotide STAT3 decoy (CS3D) was used to treat mice previously exposed to the tobacco carcinogen nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. CS3D contains a double-stranded STAT3 DNA response element sequence and interrupts STAT3 signaling by binding to STAT3 dimers, rendering them unable to initiate transcription at native STAT3 DNA binding sites. An intermittent course of CS3D decreased the development of airway preneoplasias by 42% at 1 week posttreatment, reduced the progression of preneoplasia to adenomas by 54% at 8 weeks posttreatment, and reduced the size and number of resulting lung tumors by 49.7% and 29.5%, respectively, at 20 weeks posttreatment. No toxicity was detected. A mutant cyclic oligonucleotide with no STAT3 binding ability was used as a control. Chemopreventive effects were independent of the KRAS mutational status of the tumors. In lungs harvested during and after the treatment course with CS3D, airway preneoplasias had reduced STAT3 signaling. Chemopreventive effects were accompanied by decreased VEGFA expression, ablated IL6, COX-2, and p-NF-κB, and decreased pulmonary M2 macrophages and myeloid-derived suppressor cells. Thus, downmodulation of STAT3 activity using a decoy molecule both reduced oncogenic signaling in the airway epithelium and favored a lung microenvironment with reduced immunosuppression., (©2020 American Association for Cancer Research.)
- Published
- 2020
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22. Inhibiting Pathways Predicted From a Steroid Hormone Gene Signature Yields Synergistic Antitumor Effects in NSCLC.
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Almotlak AA, Farooqui M, and Siegfried JM
- Subjects
- Animals, Cell Line, Tumor, Drug Resistance, Neoplasm, Fulvestrant pharmacology, Mice, Neoplasm Recurrence, Local, Signal Transduction, Xenograft Model Antitumor Assays, Carcinoma, Non-Small-Cell Lung drug therapy, Carcinoma, Non-Small-Cell Lung genetics, Lung Neoplasms drug therapy, Lung Neoplasms genetics
- Abstract
Introduction: Mounting evidence supports a role for estrogen signaling in NSCLC progression. We previously reported a seven-gene signature that predicts prognosis in estrogen receptor β positive (ERβ+) NSCLC. The signature defines a network comprised of ER and human EGFR-2/3 (HER2/HER3) signaling., Methods: We tested the efficacy of combining the pan-HER inhibitor, dacomitinib, with the estrogen antagonist, fulvestrant, in ERβ+ NSCLC models with differing genotypes. We assessed the potency of this combination on xenograft growth and survival of host mice, and the ability to reverse the gene signature associated with poor outcome., Results: Synergy was observed between dacomitinib and fulvestrant in three human ERβ+ NSCLC models: 201T (wild-type EGFR), A549 (KRAS mutant), and HCC827 (EGFR 19 deletion) with combination indices of 0.1-0.6. The combination, but not single agents, completely reversed the gene signature associated with poor prognosis in a mechanism that is largely mediated by activator protein 1 downregulation. In vivo, the combination also induced tumor regression and reversed the gene signature. In HCC827 xenografts treated with the combination, survival of mice was prolonged after therapy discontinuation, tumors that recurred were less aggressive, and two mechanisms of HER inhibitor resistance involving c-Met activation and PTEN loss were blocked., Conclusions: The combination of an ER blocker and a pan-HER inhibitor provides synergistic efficacy in different models of ERβ+ NSCLC. Our data support the use of this combination clinically, considering its ability to induce potent antitumor effects and produce a gene signature that predicts better clinical outcomes., (Copyright © 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)
- Published
- 2020
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23. Lung Adenocarcinoma Syndecan-2 Potentiates Cell Invasiveness.
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Tsoyi K, Osorio JC, Chu SG, Fernandez IE, De Frias SP, Sholl L, Cui Y, Tellez CS, Siegfried JM, Belinsky SA, Perrella MA, El-Chemaly S, and Rosas IO
- Subjects
- A549 Cells, Adenocarcinoma of Lung genetics, Animals, Cell Nucleus metabolism, Cell Proliferation, Gene Expression Regulation, Neoplastic, Gene Silencing, Humans, Lung Neoplasms genetics, Matrix Metalloproteinase 9 metabolism, Mice, SCID, Neoplasm Invasiveness, Syntenins metabolism, Transcription Factor RelA metabolism, Up-Regulation genetics, Adenocarcinoma of Lung pathology, Lung Neoplasms pathology, Syndecan-2 metabolism
- Abstract
Altered expression of syndecan-2 (SDC2), a heparan sulfate proteoglycan, has been associated with diverse types of human cancers. However, the mechanisms by which SDC2 may contribute to the pathobiology of lung adenocarcinoma have not been previously explored. SDC2 levels were measured in human lung adenocarcinoma samples and lung cancer tissue microarrays using immunohistochemistry and real-time PCR. To understand the role of SDC2 in vitro , SDC2 was silenced or overexpressed in A549 lung adenocarcinoma cells. The invasive capacity of cells was assessed using Matrigel invasion assays and measuring matrix metalloproteinase (MMP) 9 expression. Finally, we assessed tumor growth and metastasis of SDC2-deficient A549 cells in a xenograft tumor model. SDC2 expression was upregulated in malignant epithelial cells and macrophages obtained from human lung adenocarcinomas. Silencing of SDC2 decreased MMP9 expression and attenuated the invasive capacity of A549 lung adenocarcinoma cells. The inhibitory effect of SDC2 silencing on MMP9 expression and cell invasion was reversed by overexpression of MMP9 and syntenin-1. SDC2 silencing attenuated NF-κB p65 subunit nuclear translocation and its binding to the MMP9 promoter, which were restored by overexpression of syntenin-1. SDC2 silencing in vivo reduced tumor mass volume and metastasis. These findings suggest that SDC2 plays an important role in the invasive properties of lung adenocarcinoma cells and that its effects are mediated by syntenin-1. Thus, inhibiting SDC2 expression or activity could serve as a potential therapeutic target to treat lung adenocarcinoma.
- Published
- 2019
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24. Randomized phase II study of fulvestrant and erlotinib compared with erlotinib alone in patients with advanced or metastatic non-small cell lung cancer.
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Garon EB, Siegfried JM, Stabile LP, Young PA, Marquez-Garban DC, Park DJ, Patel R, Hu EH, Sadeghi S, Parikh RJ, Reckamp KL, Adams B, Elashoff RM, Elashoff D, Grogan T, Wang HJ, Dacic S, Brennan M, Valdes Y, Davenport S, Dubinett SM, Press MF, Slamon DJ, and Pietras RJ
- Subjects
- Aged, Antineoplastic Combined Chemotherapy Protocols adverse effects, Biomarkers, Tumor, Carcinoma, Non-Small-Cell Lung metabolism, Carcinoma, Non-Small-Cell Lung mortality, Erlotinib Hydrochloride administration & dosage, Female, Fulvestrant administration & dosage, Humans, Lung Neoplasms metabolism, Lung Neoplasms mortality, Male, Middle Aged, Neoplasm Metastasis, Neoplasm Staging, Survival Analysis, Treatment Outcome, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Carcinoma, Non-Small-Cell Lung drug therapy, Carcinoma, Non-Small-Cell Lung pathology, Erlotinib Hydrochloride therapeutic use, Lung Neoplasms drug therapy, Lung Neoplasms pathology
- Abstract
Objectives: This open-label, randomized phase II trial evaluated antitumor efficacy of an antiestrogen, fulvestrant, in combination with human epidermal growth factor receptor (EGFR) inhibitor, erlotinib, in advanced non-small cell lung cancer (NSCLC) patients., Materials and Methods: Patients with advanced or metastatic NSCLC, ECOG 0-2, previous chemotherapy unless patient refusal, and no prior EGFR-directed therapy were randomized 2:1 to erlotinib 150 mg oral daily plus 500 mg intramuscular fulvestrant on day 1, 15, 29 and every 28 days thereafter or erlotinib alone 150 mg oral daily. The primary end point was objective response rate (ORR); secondary endpoints included progression free survival (PFS) and overall survival (OS)., Results: Among 106 randomized patients, 100 received at least one dose of study drug. ORR was 16.4% (11 of 67 patients) for the combination versus 12.1% (4 of 33 patients) for erlotinib (p = 0.77). PFS median 3.5 versus 1.9 months [HR = 0.86, 95% CI (0.52-1.43), p = 0.29] and OS median 9.5 versus 5.8 months [HR = 0.92, 95% CI (0.57-1.48), p = 0.74] numerically favored the combination. In an unplanned subset analysis, among EGFR wild type patients (n = 51), but not EGFR mutant patients (n = 17), median PFS was 3.5 versus 1.7 months [HR = 0.35, 95% CI (0.14-0.86), p = 0.02] and OS was 6.2 versus 5.2 months [HR = 0.72, 95% CI (0.35-1.48), p = 0.37] for combined therapy versus erlotinib, respectively. Notably, EGFR WT patients were more likely to be hormone receptor-positive (either estrogen receptor α- and/or progesterone receptor-positive) compared to EGFR mutant patients (50% versus 9.1%, respectively) (p = 0.03). Treatment was well tolerated with predominant grade 1-2 dermatologic and gastrointestinal adverse effects., Conclusion: Addition of fulvestrant to erlotinib was well tolerated, with increased activity noted among EGFR wild type patients compared to erlotinib alone, albeit in an unplanned subset analysis., (Copyright © 2018 Elsevier B.V. All rights reserved.)
- Published
- 2018
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25. STAT3 Cyclic Decoy Demonstrates Robust Antitumor Effects in Non-Small Cell Lung Cancer.
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Njatcha C, Farooqui M, Kornberg A, Johnson DE, Grandis JR, and Siegfried JM
- Subjects
- Animals, Apoptosis drug effects, Apoptosis genetics, Carcinoma, Non-Small-Cell Lung drug therapy, Carcinoma, Non-Small-Cell Lung genetics, Cell Line, Tumor, ErbB Receptors genetics, Female, Gene Expression Regulation, Neoplastic drug effects, Humans, Lung Neoplasms drug therapy, Lung Neoplasms genetics, Mice, Nude, Mutation, Oligonucleotides, Antisense genetics, Oligonucleotides, Antisense pharmacology, STAT3 Transcription Factor genetics, Xenograft Model Antitumor Assays methods, Carcinoma, Non-Small-Cell Lung metabolism, ErbB Receptors metabolism, Lung Neoplasms metabolism, STAT3 Transcription Factor metabolism
- Abstract
Constitutively activated STAT3 plays a critical role in non-small cell lung carcinoma (NSCLC) progression by mediating proliferation and survival. STAT3 activation in normal cells is transient, making it an attractive target for NSCLC therapy. The therapeutic potential of blocking STAT3 in NSCLC was assessed utilizing a decoy approach by ligating a double-stranded 15-mer oligonucleotide that corresponds to the STAT3 response element of STAT3-target genes, to produce a cyclic STAT3 decoy (CS3D). The decoy was evaluated using NSCLC cells containing either wild-type EGFR (201T) or mutant EGFR with an additional EGFRi resistance mutation (H1975). These cells are resistant to EGFR inhibitors and require an alternate therapeutic approach. CS3D activity was compared with an inactive cyclic control oligonucleotide (CS3M) that differs by a single base pair, rendering it unable to bind to STAT3 protein. Transfection of 0.3 μmol/L of CS3D caused a 50% inhibition in proliferation in 201T and H1975 cells, relative to CS3M, and a 2-fold increase in apoptotic cells. Toxicity was minimal in normal cells. CS3D treatment caused a significant reduction of mRNA and protein expression of the STAT3 target gene c-Myc and inhibited colony formation by 70%. The active decoy decreased the nuclear pool of STAT3 compared with the mutant. In a xenograft model, treatments with CS3D (5 mg/kg) caused a potent 96.5% and 81.7% reduction in tumor growth in 201T ( P < 0.007) and H1975 models ( P < 0.0001), respectively, and reduced c-Myc and p-STAT3 proteins. Targeting STAT3 with the cyclic decoy could be an effective therapeutic strategy for NSCLC. Mol Cancer Ther; 17(9); 1917-26. ©2018 AACR ., (©2018 American Association for Cancer Research.)
- Published
- 2018
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26. Status of Agents Targeting the HGF/c-Met Axis in Lung Cancer.
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Miranda O, Farooqui M, and Siegfried JM
- Abstract
Hepatocyte growth factor (HGF) is the ligand for the tyrosine kinase receptor c-Met (Mesenchymal Epithelial Transition Factor also known as Hepatocyte Growth Factor Receptor, HGFR), a receptor with expression throughout epithelial and endothelial cell types. Activation of c-Met enhances cell proliferation, invasion, survival, angiogenesis, and motility. The c-Met pathway also stimulates tissue repair in normal cells. A body of past research shows that increased levels of HGF and/or overexpression of c-Met are associated with poor prognosis in several solid tumors, including lung cancer, as well as cancers of the head and neck, gastro-intestinal tract, breast, ovary and cervix. The HGF/c-Met signaling network is complex; both ligand-dependent and ligand-independent signaling occur. This article will provide an update on signaling through the HGF/c-Met axis, the mechanism of action of HGF/c-Met inhibitors, the lung cancer patient populations most likely to benefit, and possible mechanisms of resistance to these inhibitors. Although c-Met as a target in non-small cell lung cancer (NSCLC) showed promise based on preclinical data, clinical responses in NSCLC patients have been disappointing in the absence of MET mutation or MET gene amplification. New therapeutics that selectively target c-Met or HGF, or that target c-Met and a wider spectrum of interacting tyrosine kinases, will be discussed.
- Published
- 2018
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27. Gene Promoter Hypermethylation Detected in Sputum Predicts FEV 1 Decline and All-Cause Mortality in Smokers.
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Leng S, Diergaarde B, Picchi MA, Wilson DO, Gilliland FD, Yuan JM, Siegfried JM, and Belinsky SA
- Subjects
- Adult, Aged, Aged, 80 and over, Cohort Studies, Female, Humans, Male, Middle Aged, Respiratory Function Tests, Risk Factors, DNA Methylation genetics, Genetic Predisposition to Disease, Genetic Testing methods, Lung Neoplasms genetics, Promoter Regions, Genetic, Smoking adverse effects, Smoking genetics, Sputum chemistry
- Abstract
Rationale: Gene promoter hypermethylation detected in sputum assesses the extent of field cancerization and predicts lung cancer (LC) risk in ever-smokers. A rapid decline of FEV
1 is a major driver for development of airway obstruction., Objectives: To assess the effects of methylation of 12 genes on FEV1 decline and of FEV1 decline on subsequent LC incidence using two independent, longitudinal cohorts (i.e., LSC [Lovelace Smokers Cohort] and PLuSS [Pittsburgh Lung Screening Study])., Methods: Gene methylation was measured in sputum using two-stage nested methylation-specific PCR. The linear mixed effects model was used to assess the effects of studied variables on FEV1 decline., Measurements and Main Results: A dose-dependent relationship between number of genes methylated and FEV1 decline was identified, with smokers with three or more methylated genes having 27.8% and 10.3% faster FEV1 decline than smokers with zero to two methylated genes in the LSC and PLuSS cohort, respectively (all P < 0.01). High methylation in sputum was associated with a shorter latency for LC incidence (log-rank P = 0.0048) and worse all-cause mortality (log-rank P < 0.0001). Smokers with subsequent LC incidence had a more rapid annual decline of FEV1 (by 5.2 ml, P = 0.038) than smoker control subjects., Conclusions: Gene methylation detected in sputum predicted FEV1 decline, LC incidence, and all-cause mortality in smokers. Rapid FEV1 decline may be a risk factor for LC incidence in smokers, which may explain a greater prevalence of airway obstruction seen in patients with LC.- Published
- 2018
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28. Preclinical Evidence for Combined Use of Aromatase Inhibitors and NSAIDs as Preventive Agents of Tobacco-Induced Lung Cancer.
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Stabile LP, Farooqui M, Kanterewicz B, Abberbock S, Kurland BF, Diergaarde B, and Siegfried JM
- Subjects
- Animals, Anti-Inflammatory Agents, Non-Steroidal pharmacology, Aromatase Inhibitors pharmacology, Carcinogens, Disease Models, Animal, Female, Humans, Lung Neoplasms pathology, Mice, Anti-Inflammatory Agents, Non-Steroidal therapeutic use, Aromatase Inhibitors therapeutic use, Lung Neoplasms drug therapy, Nicotiana adverse effects
- Abstract
Introduction: A hormonal role in NSCLC development is well documented. We previously showed that the aromatase inhibitor (AI) anastrozole decreased development of tobacco carcinogen-induced lung tumors in a murine lung cancer prevention model and that aromatase and estrogen receptor were expressed in pulmonary inflammatory cells., Methods: We utilized a tobacco carcinogen-induced lung tumor mouse model by treatment with 4-(methylnitrosoamino)-1-(3-pyridyl)-1-butanone (NNK), to determine whether an AI combined with nonsteroidal anti-inflammatory drugs results in greater lung tumor prevention effects compared to single-agent treatment., Results: Combination of anastrozole (0.1 mg/kg/d) with aspirin (25 mg/kg/d) after NNK exposure resulted in significantly fewer and smaller lung tumors than did single-agent treatments and was accompanied by maximum decreases in circulating β-estradiol (E2) and interleukin-6, tumor-infiltrating macrophages, and tumoral Ki67, phospho-mitogen-activated protein kinase, phospho-signal transducer and activator of transcription 3, and interleukin-17A expression. Preneoplasia arising after combination treatment showed the lowest Sox-2 expression, suggesting an inhibitory effect on proliferative capacity in the airways by blocking both E2 and inflammation. Anastrozole combined with ibuprofen instead of aspirin also showed enhanced antitumor effects. Moreover, male mice treated with NNK that received E2 in their drinking water showed greater levels of pulmonary macrophages and inflammatory markers than did the control, confirming an E2 effect on inflammation in the microenvironment., Conclusions: Our results suggest a benefit to joint targeting of the estrogen and inflammatory pathways for NSCLC prevention. Combining AIs with nonsteroidal anti-inflammatory drugs reduces circulating E2, proinflammatory cytokines, and macrophage recruitment in the lung microenvironment after tobacco exposure. This strategy could be particularly effective in women who have underlying pulmonary inflammatory diseases., (Copyright © 2017 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)
- Published
- 2018
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29. Lung Endothelial MicroRNA-1 Regulates Tumor Growth and Angiogenesis.
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Korde A, Jin L, Zhang JG, Ramaswamy A, Hu B, Kolahian S, Guardela BJ, Herazo-Maya J, Siegfried JM, Stabile L, Pisani MA, Herbst RS, Kaminski N, Elias JA, Puchalski JT, and Takyar SS
- Subjects
- Animals, Carcinoma, Non-Small-Cell Lung blood supply, Carcinoma, Non-Small-Cell Lung metabolism, Disease Models, Animal, Lung blood supply, Lung metabolism, Lung pathology, Lung Neoplasms blood supply, Lung Neoplasms metabolism, Mice, Mice, Knockout, Neovascularization, Pathologic metabolism, Polymerase Chain Reaction, Survival Analysis, Vascular Endothelial Growth Factor A metabolism, Carcinoma, Non-Small-Cell Lung pathology, Endothelial Cells metabolism, Lung Neoplasms pathology, MicroRNAs metabolism, Neovascularization, Pathologic pathology
- Abstract
Rationale: Vascular endothelial growth factor down-regulates microRNA-1 (miR-1) in the lung endothelium, and endothelial cells play a critical role in tumor progression and angiogenesis., Objectives: To examine the clinical significance of miR-1 in non-small cell lung cancer (NSCLC) and its specific role in tumor endothelium., Methods: miR-1 levels were measured by Taqman assay. Endothelial cells were isolated by magnetic sorting. We used vascular endothelial cadherin promoter to create a vascular-specific miR-1 lentiviral vector and an inducible transgenic mouse. KRAS
G12D mut /Trp53-/- (KP) mice, lung-specific vascular endothelial growth factor transgenic mice, Lewis lung carcinoma xenografts, and primary endothelial cells were used to test the effects of miR-1., Measurements and Main Results: In two cohorts of patients with NSCLC, miR-1 levels were lower in tumors than the cancer-free tissue. Tumor miR-1 levels correlated with the overall survival of patients with NSCLC. miR-1 levels were also lower in endothelial cells isolated from NSCLC tumors and tumor-bearing lungs of KP mouse model. We examined the significance of lower miR-1 levels by testing the effects of vascular-specific miR-1 overexpression. Vector-mediated delivery or transgenic overexpression of miR-1 in endothelial cells decreased tumor burden in KP mice, reduced the growth and vascularity of Lewis lung carcinoma xenografts, and decreased tracheal angiogenesis in vascular endothelial growth factor transgenic mice. In endothelial cells, miR-1 level was regulated through phosphoinositide 3-kinase and specifically controlled proliferation, de novo DNA synthesis, and ERK1/2 activation. Myeloproliferative leukemia oncogene was targeted by miR-1 in the lung endothelium and regulated tumor growth and angiogenesis., Conclusions: Endothelial miR-1 is down-regulated in NSCLC tumors and controls tumor progression and angiogenesis.- Published
- 2017
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30. Clinical Utility of Chromosomal Aneusomy in Individuals at High Risk of Lung Cancer.
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Barón AE, Kako S, Feser WJ, Malinowski H, Merrick D, Garg K, Malkoski S, Pretzel S, Siegfried JM, Franklin WA, Miller Y, Wolf HJ, and Varella-Garcia M
- Subjects
- Aged, Chromosome Aberrations, Female, Humans, Lung Neoplasms pathology, Male, Middle Aged, Risk Factors, Lung Neoplasms genetics
- Abstract
Introduction: Low-dose computed tomography screening for lung cancer has a high false-positive rate with frequent discovery of indeterminate pulmonary nodules. Noninvasive biomarkers are needed to reduce false positives and improve risk stratification. A retrospective longitudinal evaluation was performed to assess chromosomal aneusomy in sputum by fluorescence in situ hybridization (CA-FISH) in four nested case-control studies., Methods: Receiver operating characteristic analysis resulted in two grouped cohorts: a high-risk cohort (Colorado High-Risk Cohort and Colorado Nodule Cohort [68 case patients and 69 controls]) and a screening cohort (American College of Radiology Imaging Network/National Lung Screening Trial and Pittsburgh Lung Screening Study [97 case patients and 185 controls]). The CA-FISH assay was a four-target DNA panel encompassing the EGFR and v-myc avian myelocytomatosis viral oncogene homolog (MYC) genes, and the 5p15 and centromere 6 regions or the fibroblast growth factor 1 gene (FGFR1) and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha gene (PIK3CA). A four-category scale (normal, probably normal, probably abnormal, and abnormal) was applied. Sensitivity, specificity, and positive and negative likelihood ratios (LRs) (with 95% confidence intervals [CIs]) were estimated for each cohort., Results: Sensitivity and specificity were, respectively, 0.67 (95% CI: 0.55-0.78) and 0.94 (95% CI: 0.85-0.98) for high-risk participants and 0.20 (95% CI: 0.13-0.30) and 0.84 (95% CI: 0.78-0.89) for screening participants. The positive and negative LRs were, respectively, 11.66 (95% CI: 4.44-30.63) and 0.34 (95% CI: 0.24-0.48) for high-risk participants and 1.36 (95% CI: 0.81-2.28) and 0.93 (95% CI: 0.83-1.05) for screening participants., Conclusion: The high positive LR of sputum CA-FISH indicates that it could be a useful adjunct to low-dose computed tomography for lung cancer in high-risk settings. For screening, however, its low positive LR limits clinical utility. Prospective assessment of CA-FISH in the incidentally identified indeterminate nodule setting is ongoing in the Colorado Pulmonary Nodule Biomarker Trial., (Copyright © 2017 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)
- Published
- 2017
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31. Phase 1/2 study of rilotumumab (AMG 102), a hepatocyte growth factor inhibitor, and erlotinib in patients with advanced non-small cell lung cancer.
- Author
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Tarhini AA, Rafique I, Floros T, Tran P, Gooding WE, Villaruz LC, Burns TF, Friedland DM, Petro DP, Farooqui M, Gomez-Garcia J, Gaither-Davis A, Dacic S, Argiris A, Socinski MA, Stabile LP, and Siegfried JM
- Subjects
- Adenocarcinoma genetics, Adenocarcinoma secondary, Adult, Aged, Aged, 80 and over, Antibodies, Monoclonal administration & dosage, Antibodies, Monoclonal, Humanized, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Carcinoma, Non-Small-Cell Lung genetics, Carcinoma, Non-Small-Cell Lung secondary, Carcinoma, Squamous Cell genetics, Carcinoma, Squamous Cell secondary, Disease-Free Survival, ErbB Receptors genetics, Erlotinib Hydrochloride administration & dosage, Female, Humans, Lung Neoplasms genetics, Lung Neoplasms pathology, Male, Middle Aged, Mutation, Proportional Hazards Models, Treatment Outcome, Adenocarcinoma drug therapy, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Carcinoma, Non-Small-Cell Lung drug therapy, Carcinoma, Squamous Cell drug therapy, Lung Neoplasms drug therapy
- Abstract
Background: Activation of the mesenchymal-epidermal transition factor (MET) tyrosine kinase and its ligand, hepatocyte growth factor (HGF), is implicated in resistance to epidermal growth factor receptor (EGFR) inhibitors. In this phase 1/2 trial, rilotumumab (an anti-HGF antibody) combined with erlotinib was evaluated in patients with metastatic, previously treated non-small cell lung cancer., Methods: In phase 1, a dose de-escalation design was adopted with rilotumumab starting at 15 mg/kg intravenously every 3 weeks and oral erlotinib 150 mg daily. In phase 2, the disease control rate (DCR) (according to Response Evaluation Criteria in Solid Tumors) of the combination was evaluated using a Simon 2-stage design. The biomarkers examined included 10 plasma-circulating molecules associated with the EGFR and MET pathways., Results: Without indications for de-escalation, the recommended phase 2 dose was dose level 0. Overall, 45 response-evaluable patients were enrolled (13 with squamous carcinoma, 32 with adenocarcinoma; 2 had confirmed EGFR mutations, 33 had confirmed wild-type [WT] EGFR, and 7 had KRAS mutations). The DCR for all patients was 60% (90% confidence interval [CI], 47.1%-71.3%). Median progression-free survival was 2.6 months (90% CI, 1.4-2.7 months), and median overall survival was 6.6 months (90% CI, 5.6-8.9 months). Among patients with WT EGFR, the DCR was 60.6% (90% CI, 46.3%-73.3%), median progression-free survival was 2.6 months (90% CI, 1.4-2.7 months), and median overall survival was 7.0 months (90% CI, 5.6-13.4 months). Elevated baseline levels of neuregulin 1 were associated with longer progression-free survival (hazard ratio, 0.41; 95% CI, 0.19-0.87), whereas elevated amphiregulin levels were associated with more rapid progression (hazard ratio, 2.14; 95% CI, 1.48-3.08)., Conclusions: Combined rilotumumab and erlotinib had an acceptable safety profile, and the DCR met the prespecified criteria for success. In the EGFR WT group, the DCR exceeded published reports for erlotinib alone. High circulating levels of neuregulin 1 may indicate sensitivity to this combination. Cancer 2017;123:2936-44. © 2017 American Cancer Society., (© 2017 American Cancer Society.)
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- 2017
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32. Gene methylation biomarkers in sputum as a classifier for lung cancer risk.
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Leng S, Wu G, Klinge DM, Thomas CL, Casas E, Picchi MA, Stidley CA, Lee SJ, Aisner S, Siegfried JM, Ramalingam S, Khuri FR, Karp DD, and Belinsky SA
- Abstract
CT screening for lung cancer reduces mortality, but will cost Medicare ∼2 billion dollars due in part to high false positive rates. Molecular biomarkers could augment current risk stratification used to select smokers for screening. Gene methylation in sputum reflects lung field cancerization that remains in lung cancer patients post-resection. This population was used in conjunction with cancer-free smokers to evaluate classification accuracy of a validated eight-gene methylation panel in sputum for cancer risk. Sputum from resected lung cancer patients (n=487) and smokers from Lovelace (n=1380) and PLuSS (n=718) cohorts was studied for methylation of an 8-gene panel. Area under a receiver operating characteristic curve was calculated to assess the prediction performance in logistic regressions with different sets of variables. The prevalence for methylation of all genes was significantly increased in the ECOG-ACRIN patients compared to cancer-free smokers as evident by elevated odds ratios that ranged from 1.6 to 8.9. The gene methylation panel showed lung cancer prediction accuracy of 82-86% and with addition of clinical variables improved to 87-90%. With sensitivity at 95%, specificity increased from 25% to 54% comparing clinical variables alone to their inclusion with methylation. The addition of methylation biomarkers to clinical variables would reduce false positive screens by ruling out one-third of smokers eligible for CT screening and could increase cancer detection rates through expanding risk assessment criteria., Competing Interests: CONFLICTS OF INTEREST The authors declare no competing financial interests.
- Published
- 2017
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33. Interaction between the estrogen receptor and fibroblast growth factor receptor pathways in non-small cell lung cancer.
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Siegfried JM, Farooqui M, Rothenberger NJ, Dacic S, and Stabile LP
- Subjects
- Animals, Antineoplastic Agents, Hormonal pharmacology, Benzamides pharmacology, Biomarkers, Carcinoma, Non-Small-Cell Lung pathology, Cell Line, Tumor, Cell Proliferation drug effects, Disease Models, Animal, Estradiol analogs & derivatives, Estradiol pharmacology, Estrogens metabolism, Female, Fibroblast Growth Factors biosynthesis, Fibroblast Growth Factors metabolism, Fulvestrant, Humans, Ligands, Lung Neoplasms pathology, Mice, Neoplastic Stem Cells metabolism, Piperazines pharmacology, Protein Binding, Pyrazoles pharmacology, Receptors, Estrogen antagonists & inhibitors, Receptors, Fibroblast Growth Factor antagonists & inhibitors, Xenograft Model Antitumor Assays, Carcinoma, Non-Small-Cell Lung metabolism, Lung Neoplasms metabolism, Receptors, Estrogen metabolism, Receptors, Fibroblast Growth Factor metabolism, Signal Transduction drug effects
- Abstract
The estrogen receptor (ER) promotes non-small cell lung cancer (NSCLC) proliferation. Since fibroblast growth factors (FGFs) are known regulators of stem cell markers in ER positive breast cancer, we investigated whether a link between the ER, FGFs, and stem cell markers exists in NSCLC. In lung preneoplasias and adenomas of tobacco carcinogen exposed mice, the anti-estrogen fulvestrant and/or the aromatase inhibitor anastrozole blocked FGF2 and FGF9 secretion, and reduced expression of the stem cell markers SOX2 and nanog. Mice administered β-estradiol during carcinogen exposure showed increased FGF2, FGF9, SOX2, and Nanog expression in airway preneoplasias. In normal FGFR1 copy number NSCLC cell lines, multiple FGFR receptors were expressed and secreted several FGFs. β-estradiol caused enhanced FGF2 release, which was blocked by fulvestrant. Upon co-inhibition of ER and FGFRs using fulvestrant and the pan-FGFR inhibitor AZD4547, phosphorylation of FRS2, the FGFR docking protein, was maximally reduced, and enhanced anti-proliferative effects were observed. Combined AZD4547 and fulvestrant enhanced lung tumor xenograft growth inhibition and decreased Ki67 and stem cell marker expression. To verify a link between ERβ, the predominant ER in NSCLC, and FGFR signaling in patient tumors, mRNA analysis was performed comparing high versus low ERβ expressing tumors. The top differentially expressed genes in high ERβ tumors involved FGF signaling and human embryonic stem cell pluripotency. These results suggest interaction between the ER and FGFR pathways in NSCLC promotes a stem-like state. Combined FGFR and ER inhibition may increase the efficacy of FGFR inhibitors for NSCLC patients lacking FGFR genetic alterations.
- Published
- 2017
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34. Myeloid STAT3 Promotes Lung Tumorigenesis by Transforming Tumor Immunosurveillance into Tumor-Promoting Inflammation.
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Zhou J, Qu Z, Sun F, Han L, Li L, Yan S, Stabile LP, Chen LF, Siegfried JM, and Xiao G
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- Animals, CD8 Antigens deficiency, Cell Movement genetics, Cell Survival genetics, Cell Transformation, Neoplastic genetics, Cytotoxicity, Immunologic, Disease Models, Animal, Humans, Inflammation complications, Inflammation genetics, Inflammation metabolism, Inflammation pathology, Interferon-gamma metabolism, Lung Neoplasms mortality, Lung Neoplasms pathology, Macrophages immunology, Macrophages metabolism, Mice, Mice, Knockout, Myeloid Cells immunology, Myeloid-Derived Suppressor Cells immunology, Myeloid-Derived Suppressor Cells metabolism, Prognosis, STAT3 Transcription Factor genetics, T-Lymphocyte Subsets immunology, T-Lymphocyte Subsets metabolism, Cell Transformation, Neoplastic metabolism, Immunologic Surveillance genetics, Immunologic Surveillance immunology, Lung Neoplasms etiology, Lung Neoplasms metabolism, Myeloid Cells metabolism, STAT3 Transcription Factor metabolism
- Abstract
One of the most fundamental and challenging questions in the cancer field is how immunity in patients with cancer is transformed from tumor immunosurveillance to tumor-promoting inflammation. Here, we identify the transcription factor STAT3 as the culprit responsible for this pathogenic event in lung cancer development. We found that antitumor type 1 CD4
+ T-helper (Th1) cells and CD8+ T cells were directly counter balanced in lung cancer development with tumor-promoting myeloid-derived suppressor cells (MDSCs) and suppressive macrophages, and that activation of STAT3 in MDSCs and macrophages promoted tumorigenesis through pulmonary recruitment and increased resistance of suppressive cells to CD8+ T cells, enhancement of cytotoxicity toward CD4+ and CD8+ T cells, induction of regulatory T cell (Treg), inhibition of dendritic cells (DC), and polarization of macrophages toward the M2 phenotype. The deletion of myeloid STAT3 boosted antitumor immunity and suppressed lung tumorigenesis. These findings increase our understanding of immune programming in lung tumorigenesis and provide a mechanistic basis for developing STAT3-based immunotherapy against this and other solid tumors. Cancer Immunol Res; 5(3); 257-68. ©2017 AACR ., (©2017 American Association for Cancer Research.)- Published
- 2017
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35. KRAS and TP53 mutations in bronchoscopy samples from former lung cancer patients.
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Gao W, Jin J, Yin J, Land S, Gaither-Davis A, Christie N, Luketich JD, Siegfried JM, and Keohavong P
- Subjects
- Aged, Bronchoscopy, Disease-Free Survival, Female, Humans, Lung Neoplasms diagnosis, Lung Neoplasms pathology, Male, Middle Aged, Neoplasm Recurrence, Local diagnosis, Neoplasm Recurrence, Local genetics, Neoplasm Recurrence, Local pathology, Smoking adverse effects, Lung pathology, Lung Neoplasms genetics, Mutation, Proto-Oncogene Proteins p21(ras) genetics, Tumor Suppressor Protein p53 genetics
- Abstract
Mutations in the KRAS and TP53 genes have been found frequently in lung tumors and specimens from individuals at high risk for lung cancer and have been suggested as predictive markers for lung cancer. In order to assess the prognostic value of these two genes' mutations in lung cancer recurrence, we analyzed mutations in codon 12 of the KRAS gene and in hotspot codons of the TP53 gene in 176 bronchial biopsies obtained from 77 former lung cancer patients. Forty-seven patients (61.0%) showed mutations, including 35/77 (45.5%) in the KRAS gene and 25/77 (32.5%) in the TP53 gene, among them 13/77 (16.9%) had mutations in both genes. When grouped according to past or current smoking status, a higher proportion of current smokers showed mutations, in particular those in the TP53 gene (P = 0.07), compared with ex-smokers. These mutations were found in both abnormal lesions (8/20 or 40%) and histologically normal tissues (70/156 or 44.9%) (P = 0.812). They consisted primarily of G to A transition and G to T transversion in both the KRAS (41/56 or 73.2%) and TP53 (24/34 or 70.6%) genes, consistent with mutations found in lung tumors of smoking lung cancer patients. Overall, recurrence-free survival (RFS) among all subjects could be explained by age at diagnosis, tumor stage, tumor subtype, and smoking (P < 0.05, Cox proportional hazard). Therefore, KRAS and TP53 mutations were frequently detected in bronchial tissues of former lung cancer patients. However, the presence of mutation of bronchial biopsies was not significantly associated with a shorter RFS time. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)
- Published
- 2017
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36. ATM protein is deficient in over 40% of lung adenocarcinomas.
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Villaruz LC, Jones H, Dacic S, Abberbock S, Kurland BF, Stabile LP, Siegfried JM, Conrads TP, Smith NR, O'Connor MJ, Pierce AJ, and Bakkenist CJ
- Subjects
- Adenocarcinoma genetics, Adenocarcinoma of Lung, Adult, Aged, Aged, 80 and over, Animals, Ataxia Telangiectasia Mutated Proteins metabolism, Carcinoma, Non-Small-Cell Lung genetics, Carcinoma, Non-Small-Cell Lung metabolism, Cisplatin pharmacology, DNA Damage, Female, Humans, Immunohistochemistry, Lung Neoplasms genetics, Male, Mice, Middle Aged, Neoplasm Transplantation, Phosphorylation, Tissue Array Analysis, Treatment Outcome, Adenocarcinoma metabolism, Ataxia Telangiectasia Mutated Proteins genetics, Lung Neoplasms metabolism
- Abstract
Lung cancer is the leading cause of cancer-related mortality in the USA and worldwide, and of the estimated 1.2 million new cases of lung cancer diagnosed every year, over 30% are lung adenocarcinomas. The backbone of 1st-line systemic therapy in the metastatic setting, in the absence of an actionable oncogenic driver, is platinum-based chemotherapy. ATM and ATR are DNA damage signaling kinases activated at DNA double-strand breaks (DSBs) and stalled and collapsed replication forks, respectively. ATM protein is lost in a number of cancer cell lines and ATR kinase inhibitors synergize with cisplatin to resolve xenograft models of ATM-deficient lung cancer. We therefore sought to determine the frequency of ATM loss in a tissue microarray (TMA) of lung adenocarcinoma. Here we report the validation of a commercial antibody (ab32420) for the identification of ATM by immunohistochemistry and estimate that 61 of 147 (41%, 95% CI 34%-50%) cases of lung adenocarcinoma are negative for ATM protein expression. As a positive control for ATM staining, nuclear ATM protein was identified in stroma and immune infiltrate in all evaluable cases. ATM loss in lung adenocarcinoma was not associated with overall survival. However, our preclinical findings in ATM-deficient cell lines suggest that ATM could be a predictive biomarker for synergy of an ATR kinase inhibitor with standard-of-care cisplatin. This could improve clinical outcome in 100,000's of patients with ATM-deficient lung adenocarcinoma every year., Competing Interests: None. Helen Jones, Neil Smith, Mark O'Connor and Andrew Pierce are employees of AstraZeneca as clearly stated in author affiliations.
- Published
- 2016
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37. A prospective and retrospective analysis of smoking behavior changes in ever smokers with high risk for lung cancer from New Mexico and Pennsylvania.
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Leng S, Weissfeld JL, Picchi MA, Styn MA, Claus ED, Clark VP, Wu G, Thomas CL, Gilliland FD, Yuan J, Siegfried JM, and Belinsky SA
- Abstract
Cigarette smoking is the leading preventable cause of death worldwide. The aim of this study is to conduct a prospective and retrospective analysis of smoking behavior changes in the Lovelace Smokers Cohort (LSC) and the Pittsburgh Lung Screening Study cohort (PLuSS). Area under the curve (AUC) for risk models predicting relapse based on demographic, smoking, and relevant clinical variables was 0.93 and 0.79 in LSC and PLuSS, respectively. The models for making a quit attempt had limited prediction ability in both cohorts (AUC≤0.62). We identified an ethnic disparity in adverse smoking behavior change that Hispanic smokers were less likely to make a quit attempt and were more likely to relapse after a quit attempt compared to non-Hispanic Whites. SNPs at 15q25 and 11p14 loci were associated with risk for smoking relapse in the LSC. Rs6495308 at 15q25 has a large difference in minor allele frequency between non-Hispanic Whites and Hispanics (0.46 versus 0.23, P<0.0001) and was associated with risk for ever relapse at same magnitude between the two ethnic groups (OR=1.36, 95% CI=1.10 to 1.67 versus 1.59, 95% CI=1.00 to 2.53, P=0.81). In summary, the risk prediction model established in LSC and PLuSS provided an excellent to outstanding distinguishing for abstainers who will or will not relapse. The ethnic disparity in adverse smoking behavior between Hispanics and non-Hispanic Whites may be at least partially explained by the sequence variants at 15q25 locus that contains multiple nicotine acetylcholine receptors.
- Published
- 2016
38. NF-κB1 p105 suppresses lung tumorigenesis through the Tpl2 kinase but independently of its NF-κB function.
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Sun F, Qu Z, Xiao Y, Zhou J, Burns TF, Stabile LP, Siegfried JM, and Xiao G
- Subjects
- Animals, Cell Line, Tumor, Enzyme Stability drug effects, Enzyme Stability genetics, Gene Knockout Techniques, Genes, ras genetics, Homeostasis drug effects, Homeostasis genetics, Humans, Lung drug effects, Lung pathology, MAP Kinase Kinase Kinases deficiency, MAP Kinase Kinase Kinases genetics, Mice, Mutation, NF-kappa B p50 Subunit deficiency, NF-kappa B p50 Subunit genetics, Proto-Oncogene Proteins deficiency, Proto-Oncogene Proteins genetics, Signal Transduction drug effects, Signal Transduction genetics, Urethane pharmacology, Carcinogenesis chemically induced, Carcinogenesis genetics, Lung Neoplasms pathology, MAP Kinase Kinase Kinases metabolism, NF-kappa B p50 Subunit metabolism, Proto-Oncogene Proteins metabolism
- Abstract
Nuclear factor-κB (NF-κB) is generally believed to be pro-tumorigenic. Here we report a tumor-suppressive function for NF-κB1, the prototypical member of NF-κB. While NF-κB1 downregulation is associated with high lung cancer risk in humans and poor patient survival, NF-κB1-deficient mice are more vulnerable to lung tumorigenesis induced by the smoke carcinogen, urethane. Notably, the tumor-suppressive function of NF-κB1 is independent of its classical role as an NF-κB factor, but instead through stabilization of the Tpl2 kinase. NF-κB1-deficient tumors exhibit 'normal' NF-κB activity, but a decreased protein level of Tpl2. Reconstitution of Tpl2 or the NF-κB1 p105, but not p50 (the processed product of p105), inhibits the tumorigenicity of NF-κB1-deficient lung tumor cells. Remarkably, Tpl2-knockout mice resemble NF-κB1 knockouts in urethane-induced lung tumorigenesis. Mechanistic studies indicate that p105/Tpl2 signaling is required for suppressing urethane-induced lung damage and inflammation, and activating mutations of the K-Ras oncogene. These studies reveal an unexpected, NF-κB-independent but Tpl2-depenednt role of NF-κB1 in lung tumor suppression. These studies also reveal a previously unexplored role of p105/Tpl2 signaling in lung homeostasis.
- Published
- 2016
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39. Lung Cancer Risk Prediction Using Common SNPs Located in GWAS-Identified Susceptibility Regions.
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Weissfeld JL, Lin Y, Lin HM, Kurland BF, Wilson DO, Fuhrman CR, Pennathur A, Romkes M, Nukui T, Yuan JM, Siegfried JM, and Diergaarde B
- Subjects
- Aged, Aged, 80 and over, Female, Humans, Male, Middle Aged, Risk Factors, Genome-Wide Association Study methods, Lung Neoplasms genetics, Polymorphism, Single Nucleotide genetics
- Abstract
Introduction: Genome-wide association studies (GWAS) have consistently identified specific lung cancer susceptibility regions. We evaluated the lung cancer-predictive performance of single-nucleotide polymorphisms (SNPs) in these regions., Methods: Lung cancer cases (N = 778) and controls (N = 1166) were genotyped for 77 SNPs located in GWAS-identified lung cancer susceptibility regions. Variable selection and model development used stepwise logistic regression and decision-tree analyses. In a subset nested in the Pittsburgh Lung Screening Study, change in area under the receiver operator characteristic curve and net reclassification improvement were used to compare predictions made by risk factor models with and without genetic variables., Results: Variable selection and model development kept two SNPs in each of three GWAS regions, rs2736100 and rs7727912 in 5p15.33, rs805297 and rs1802127 in 6p21.33, and rs8034191 and rs12440014 in 15q25.1. The ratio of cases to controls was three times higher among subjects with a high-risk genotype in every one as opposed to none of the three GWAS regions (odds ratio, 3.14; 95% confidence interval, 2.02-4.88; adjusted for sex, age, and pack-years). Adding a three-level classified count of GWAS regions with high-risk genotypes to an age and smoking risk factor-only model improved lung cancer prediction by a small amount: area under the receiver operator characteristic curve, 0.725 versus 0.717 (p = 0.056); overall net reclassification improvement was 0.052 across low-, intermediate-, and high- 6-year lung cancer risk categories (<3.0%, 3.0%-4.9%, ≥ 5.0%)., Conclusion: Specifying genotypes for SNPs in three GWAS-identified susceptibility regions improved lung cancer prediction, but probably by an extent too small to affect disease control practice.
- Published
- 2015
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40. Expression of PAM50 Genes in Lung Cancer: Evidence that Interactions between Hormone Receptors and HER2/HER3 Contribute to Poor Outcome.
- Author
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Siegfried JM, Lin Y, Diergaarde B, Lin HM, Dacic S, Pennathur A, Weissfeld JL, Romkes M, Nukui T, and Stabile LP
- Subjects
- Aged, Carcinoma, Non-Small-Cell Lung genetics, Carcinoma, Non-Small-Cell Lung mortality, Cohort Studies, Estrogen Receptor beta genetics, Female, Humans, Lung Neoplasms genetics, Lung Neoplasms mortality, Male, Middle Aged, Protein Binding physiology, Receptor, ErbB-2 genetics, Receptor, ErbB-3 genetics, Survival Rate trends, Tissue Array Analysis trends, Treatment Outcome, Carcinoma, Non-Small-Cell Lung metabolism, Estrogen Receptor beta biosynthesis, Gene Expression Regulation, Neoplastic, Lung Neoplasms metabolism, Receptor, ErbB-2 biosynthesis, Receptor, ErbB-3 biosynthesis
- Abstract
Non-small cell lung cancers (NSCLCs) frequently express estrogen receptor (ER) β, and estrogen signaling is active in many lung tumors. We investigated the ability of genes contained in the prediction analysis of microarray 50 (PAM50) breast cancer risk predictor gene signature to provide prognostic information in NSCLC. Supervised principal component analysis of mRNA expression data was used to evaluate the ability of the PAM50 panel to provide prognostic information in a stage I NSCLC cohort, in an all-stage NSCLC cohort, and in The Cancer Genome Atlas data. Immunohistochemistry was used to determine status of ERβ and other proteins in lung tumor tissue. Associations with prognosis were observed in the stage I cohort. Cross-validation identified seven genes that, when analyzed together, consistently showed survival associations. In pathway analysis, the seven-gene panel described one network containing the ER and progesterone receptor, as well as human epidermal growth factor receptor (HER)2/HER3 and neuregulin-1. NSCLC cases also showed a significant association between ERβ and HER2 protein expression. Cases positive for HER2 expression were more likely to express HER3, and ERβ-positive cases were less likely to be both HER2 and HER3 negative. Prognostic ability of genes in the PAM50 panel was verified in an ERβ-positive cohort representing all NSCLC stages. In The Cancer Genome Atlas data sets, the PAM50 gene set was prognostic in both adenocarcinoma and squamous cell carcinoma, whereas the seven-gene panel was prognostic only in squamous cell carcinoma. Genes in the PAM50 panel, including those linking ER and HER2, identify lung cancer patients at risk for poor outcome, especially among ERβ-positive cases and squamous cell carcinoma., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2015
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41. Functional analyses of ATM, ATR and Fanconi anemia proteins in lung carcinoma : ATM, ATR and FA in lung carcinoma.
- Author
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Beumer JH, Fu KY, Anyang BN, Siegfried JM, and Bakkenist CJ
- Subjects
- Antineoplastic Agents pharmacology, Carcinoma genetics, Cell Death drug effects, Cell Death radiation effects, Cell Line, Tumor, Dose-Response Relationship, Drug, Enzyme Activation, Humans, Lung Neoplasms genetics, Protein Kinase Inhibitors pharmacology, Radiation, Ionizing, Signal Transduction, Ataxia Telangiectasia Mutated Proteins metabolism, Carcinoma metabolism, Fanconi Anemia Complementation Group Proteins metabolism, Lung Neoplasms metabolism
- Abstract
Background: ATM and ATR are kinases implicated in a myriad of DNA-damage responses. ATM kinase inhibition radiosensitizes cells and selectively kills cells with Fanconi anemia (FA) gene mutations. ATR kinase inhibition sensitizes cells to agents that induce replication stress and selectively kills cells with ATM and TP53 mutations. ATM mutations and FANCF promoter-methylation are reported in lung carcinomas., Methods: We undertook functional analyses of ATM, ATR, Chk1 and FA proteins in lung cancer cell lines. We included Calu6 that is reported to be FANCL-deficient. In addition, the cancer genome atlas (TCGA) database was interrogated for alterations in: 1) ATM, MRE11A, RAD50 and NBN; 2) ATR, ATRIP and TOPBP1; and 3) 15 FA genes., Results: No defects in ATM, ATR or Chk1 kinase activation, or FANCD2 monoubiquitination were identified in the lung cancer cell lines examined, including Calu6, and major alterations in these pathways were not identified in the TCGA database. Cell lines were radiosensitized by ATM kinase inhibitor KU60019, but no cell killing by ATM kinase inhibitor alone was observed. While no synergy between gemcitabine or carboplatin and ATR kinase inhibitor ETP-46464 was observed, synergy between gemcitabine and Chk1 kinase inhibitor UCN-01 was observed in 54 T, 201 T and H460, and synergy between carboplatin and Chk1 kinase inhibitor was identified in 201 T and 239 T. No interactions between ATM, ATR and FA activation were observed by either ATM or ATR kinase inhibition in the lung cancer cell lines., Conclusions: Analyses of ATM serine 1981 and Chk1 serine 345 phosphorylation, and FANCD2 monoubiquitination revealed that ATM and ATR kinase activation and FA pathway signaling are intact in the lung cancer cell lines examined. As such, these posttranslational modifications may have utility as biomarkers for the integrity of DNA damage signaling pathways in lung cancer. Different sensitization profiles between gemcitabine and carboplatin and ATR kinase inhibitor ETP-46464 and Chk1 kinase inhibitor UCN-01 were observed and this should be considered in the rationale for Phase I clinical trial design with ATR kinase inhibitors.
- Published
- 2015
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42. Epigenetic Repression of CCDC37 and MAP1B Links Chronic Obstructive Pulmonary Disease to Lung Cancer.
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Tessema M, Yingling CM, Picchi MA, Wu G, Liu Y, Weissfeld JL, Siegfried JM, Tesfaigzi Y, and Belinsky SA
- Subjects
- Adult, Aged, Aged, 80 and over, Female, Gene Expression, Genome-Wide Association Study, Humans, Lung chemistry, Male, Middle Aged, Adenocarcinoma genetics, DNA Methylation genetics, Epigenetic Repression, Lung Neoplasms genetics, Microtubule-Associated Proteins genetics, Pulmonary Disease, Chronic Obstructive genetics
- Abstract
Introduction: Lung cancer and chronic obstructive pulmonary disease (COPD) share environmental risk factors. COPD also increases the risk of lung cancer; however, the molecular mechanisms are unclear., Methods: An epigenome-wide association study of lung tumors and cancer-free lung tissue (CFLT) pairs from non-small-cell lung cancer cases with (n = 18) or without (n = 17) COPD was conducted using the HumanMethylation450 beadchip (HM450K). COPD-associated methylation of top-ranked genes was confirmed in a larger sample set, independently validated, and their potential as sputum-based biomarkers was investigated., Results: Methylation of CCDC37 and MAP1B was more prevalent in lung tumors from COPD than non-COPD cases [54 of 71 (76%) versus 20 of 46 (43%), p = 0.0013] and [48 of 71 (68%) versus 17 of 46 (37%), p = 0.0035], respectively, after adjustment for age, sex, smoking status, and tumor histology. HM450K probes across CCDC37 and MAP1B promoters showed higher methylation in tumors than CFLT with the highest methylation seen in tumors from COPD cases (p < 0.05). These results were independently validated using The Cancer Genome Atlas data. CCDC37 methylation was more prevalent in sputum from COPD than non-COPD smokers (p < 0.005) from two cohorts. CCDC37 and MAP1B expression was dramatically repressed in tumors and CFLT from COPD than non-COPD cases, p less than 0.02., Conclusions: The reduced expression of CCDC37 and MAP1B associated with COPD likely predisposes these genes to methylation that in turn, may contribute to lung cancer.
- Published
- 2015
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43. 15q12 variants, sputum gene promoter hypermethylation, and lung cancer risk: a GWAS in smokers.
- Author
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Leng S, Liu Y, Weissfeld JL, Thomas CL, Han Y, Picchi MA, Edlund CK, Willink RP, Gaither Davis AL, Do KC, Nukui T, Zhang X, Burki EA, Van Den Berg D, Romkes M, Gauderman WJ, Crowell RE, Tesfaigzi Y, Stidley CA, Amos CI, Siegfried JM, Gilliland FD, and Belinsky SA
- Subjects
- Adult, Aged, Chromosomes, Human, Pair 15 genetics, Female, Gene Frequency, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Haplotypes, Humans, Logistic Models, Male, Middle Aged, Reproducibility of Results, Risk, Chromosomes, Human, Pair 15 metabolism, DNA Methylation, Lung Neoplasms genetics, Polymorphism, Single Nucleotide, Promoter Regions, Genetic, Smoking adverse effects, Sputum
- Abstract
Background: Lung cancer is the leading cause of cancer-related mortality worldwide. Detection of promoter hypermethylation of tumor suppressor genes in exfoliated cells from the lung provides an assessment of field cancerization that in turn predicts lung cancer. The identification of genetic determinants for this validated cancer biomarker should provide novel insights into mechanisms underlying epigenetic reprogramming during lung carcinogenesis., Methods: A genome-wide association study using generalized estimating equations and logistic regression models was conducted in two geographically independent smoker cohorts to identify loci affecting the propensity for cancer-related gene methylation that was assessed by a 12-gene panel interrogated in sputum. All statistical tests were two-sided., Results: Two single nucleotide polymorphisms (SNPs) at 15q12 (rs73371737 and rs7179575) that drove gene methylation were discovered and replicated with rs73371737 reaching genome-wide significance (P = 3.3×10(-8)). A haplotype carrying risk alleles from the two 15q12 SNPs conferred 57% increased risk for gene methylation (P = 2.5×10(-9)). Rs73371737 reduced GABRB3 expression in lung cells and increased risk for smoking-induced chronic mucous hypersecretion. Furthermore, subjects with variant homozygote of rs73371737 had a two-fold increase in risk for lung cancer (P = .0043). Pathway analysis identified DNA double-strand break repair by homologous recombination (DSBR-HR) as a major pathway affecting susceptibility for gene methylation that was validated by measuring chromatid breaks in lymphocytes challenged by bleomycin., Conclusions: A functional 15q12 variant was identified as a risk factor for gene methylation and lung cancer. The associations could be mediated by GABAergic signaling that drives the smoking-induced mucous cell metaplasia. Our findings also substantiate DSBR-HR as a critical pathway driving epigenetic gene silencing., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2015
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44. Matrix metalloproteinase-19 promotes metastatic behavior in vitro and is associated with increased mortality in non-small cell lung cancer.
- Author
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Yu G, Herazo-Maya JD, Nukui T, Romkes M, Parwani A, Juan-Guardela BM, Robertson J, Gauldie J, Siegfried JM, Kaminski N, and Kass DJ
- Subjects
- Carcinoma, Non-Small-Cell Lung mortality, Carcinoma, Non-Small-Cell Lung pathology, Cell Death, Cell Line, Tumor, Down-Regulation genetics, Epithelial-Mesenchymal Transition genetics, Female, Gene Expression Regulation, Neoplastic genetics, Humans, Lung Neoplasms mortality, Male, MicroRNAs genetics, Neoplasm Invasiveness genetics, Survival Rate, Apoptosis genetics, Carcinoma, Non-Small-Cell Lung genetics, Carcinoma, Non-Small-Cell Lung secondary, Lung Neoplasms genetics, Lung Neoplasms pathology, Matrix Metalloproteinases, Secreted genetics
- Abstract
Rationale: Lung cancer is the leading cause of cancer death in both men and women in the United States and worldwide. Matrix metalloproteinases (MMPs) have been implicated in the development and progression of lung cancer, but their role in the molecular pathogenesis of lung cancer remains unclear. We have found that MMP19, a relatively novel member of the MMP family, is overexpressed in lung tumors when compared with control subjects., Objectives: To test the hypothesis that MMP19 plays a significant role in the development and progression of non-small cell lung cancer (NSCLC)., Methods: We have analyzed lung cancer gene expression data, immunostained lung tumors for MMP19, and performed in vitro assays to test the effects of MMP19 in NSCLC cells., Measurements and Main Results: We found that MMP19 gene and protein expression is increased in lung cancer tumors compared with adjacent and histologically normal lung tissues. In three independent datasets, increased MMP19 gene expression conferred a poorer prognosis in NSCLC. In vitro, we found that overexpression of MMP19 promotes epithelial-mesenchymal transition, migration, and invasiveness in multiple NSCLC cell lines. Overexpression of MMP19 with a mutation at the catalytic site did not impair epithelial-mesenchymal transition or expression of prometastasis genes. We also found that miR-30 isoforms, a microRNA family predicted to target MMP19, is markedly down-regulated in human lung cancer and regulates MMP19 expression., Conclusions: Taken together, these findings suggest that MMP19 is associated with the development and progression of NSCLC and may be a potential biomarker of disease severity and outcome.
- Published
- 2014
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45. Inherited variation in the ATP-binding cassette transporter ABCB1 and survival after chemotherapy for stage III-IV lung cancer.
- Author
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Weissfeld JL, Diergaarde B, Nukui T, Buch S, Pennathur A, Socinski MA, Siegfried JM, and Romkes M
- Subjects
- ATP Binding Cassette Transporter, Subfamily B genetics, ATP Binding Cassette Transporter, Subfamily B metabolism, Aged, Aged, 80 and over, Alleles, Carcinoma, Non-Small-Cell Lung diagnosis, Carcinoma, Non-Small-Cell Lung drug therapy, Female, Follow-Up Studies, Genetic Predisposition to Disease, Genotype, Humans, Lung Neoplasms drug therapy, Lung Neoplasms mortality, Male, Middle Aged, Pennsylvania epidemiology, Retrospective Studies, Survival Rate trends, Antineoplastic Agents therapeutic use, Carcinoma, Non-Small-Cell Lung genetics, DNA, Neoplasm genetics, Lung Neoplasms genetics, Neoplasm Staging, Polymorphism, Genetic
- Abstract
Background: The ATP-binding cassette transporter gene ABCB1 and the glutathione S-transferase gene GSTP1 code for a multidrug resistance protein and for a detoxifying phase II metabolic enzyme, respectively, with substrate specificities that include chemotherapy drugs often used to treat lung cancer., Methods: We genotyped 11 ABCB1 and eight GSTP1 single nucleotide polymorphisms (SNPs) in 698 white lung cancer patients (all current or former cigarette smokers) and used log-rank test statistics and proportional hazards regression to evaluate associations between SNP genotype and survival., Results: Using data from all 698 cases, one SNP in ABCB1 (rs2235013) was statistically significantly associated with overall survival (p = 0.038, log-rank test). Chemotherapy and stage jointly (p = 0.025) significantly modified the association between rs2235013 and survival, with statistically significant (p = 0.013, log-rank test) association observed in the subgroup of stage III to IV lung cancer patients who received chemotherapy as part of their first course of treatment (n = 160; 93.1% nonsmall cell). Patients who inherited the minor T allele at ABCB1 rs2235013 experienced better overall survival and recurrence-free survival (hazard ratio, per minor T allele, [95% confidence interval]: 0.66 [0.49-0.90] and 0.55 [0.31-0.95], respectively; adjusted for year of diagnosis, sex, age at diagnosis, cigarette pack years, and stage). In addition, in the advanced stage chemotherapy-treated subgroup, four ABCB1 SNPs (rs6949448, rs2235046, rs1128503, and rs10276036) in mutual high linkage disequilibrium with rs2235013 and an independent ABCB1 SNP (rs1045642) showed statistically significant association (p < 0.05) with survival., Conclusions: Inherited variation in ABCB1 may affect survival specifically in advanced stage lung cancer patients who receive chemotherapy.
- Published
- 2014
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46. Co-targeting c-Met and COX-2 leads to enhanced inhibition of lung tumorigenesis in a murine model with heightened airway HGF.
- Author
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Stabile LP, Rothstein ME, Gubish CT, Cunningham DE, Lee N, and Siegfried JM
- Subjects
- Animals, Blotting, Western, Carcinoma, Non-Small-Cell Lung metabolism, Carcinoma, Non-Small-Cell Lung pathology, Cell Line, Tumor, Cell Proliferation, Cell Transformation, Neoplastic, Cyclooxygenase 2 biosynthesis, Hepatocyte Growth Factor biosynthesis, Humans, Immunohistochemistry, Lung Neoplasms metabolism, Lung Neoplasms pathology, Mice, Mice, Transgenic, Signal Transduction, Carcinoma, Non-Small-Cell Lung genetics, Cyclooxygenase 2 genetics, DNA, Neoplasm genetics, Gene Expression Regulation, Neoplastic, Hepatocyte Growth Factor genetics, Lung Neoplasms genetics, Neoplasms, Experimental
- Abstract
Background: The hepatocyte growth factor (HGF)/c-Met pathway is often dysregulated in non-small-cell lung cancer (NSCLC). HGF activation of c-Met induces cyclooxygenase-2 (COX-2), resulting in downstream stimulation by prostaglandin E2 of additional pathways. Targeting both c-Met and COX-2 might lead to enhanced antitumor effects by blocking signaling upstream and downstream of c-Met., Methods: Effects of crizotinib or celecoxib alone or in combination were tested in NSCLC cells in vitro and in mice transgenic for airway expression of human HGF., Results: Proliferation and invasion of NSCLC cells treated with a combination of crizotinib and celecoxib were significantly lower compared with single treatments. Transgenic mice showed enhanced COX-2 expression localized to preneoplastic areas following exposure to the tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, which was not present without carcinogen exposure. This shows that COX-2 activity is present during lung tumor development in a high HGF environment. After 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone treatment, a significant decrease in the number of lung tumors per animal was observed after 13-week treatments of crizotinib, celecoxib, or the combination compared with placebo (p < 0.001). With combination treatment, the number of tumors was also significantly lower than single agent treatment (p < 0.001). In the resulting lung tumors, P-c-Met, COX-2, prostaglandin E2, and P-MAPK were significantly downmodulated by combination treatment compared with single treatment. Expression of the epithelial-mesenchymal transition markers E-cadherin and snail was also modulated by combination treatment., Conclusions: In the presence of high HGF, dual inhibition of c-Met and COX-2 may enhance antitumor effects. This combination may have clinical potential in NSCLCs with high HGF/c-Met expression or epithelial-mesenchymal transition phenotype.
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- 2014
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47. Validation of a blood protein signature for non-small cell lung cancer.
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Mehan MR, Williams SA, Siegfried JM, Bigbee WL, Weissfeld JL, Wilson DO, Pass HI, Rom WN, Muley T, Meister M, Franklin W, Miller YE, Brody EN, and Ostroff RM
- Abstract
Background: CT screening for lung cancer is effective in reducing mortality, but there are areas of concern, including a positive predictive value of 4% and development of interval cancers. A blood test that could manage these limitations would be useful, but development of such tests has been impaired by variations in blood collection that may lead to poor reproducibility across populations., Results: Blood-based proteomic profiles were generated with SOMAscan technology, which measured 1033 proteins. First, preanalytic variability was evaluated with Sample Mapping Vectors (SMV), which are panels of proteins that detect confounders in protein levels related to sample collection. A subset of well collected serum samples not influenced by preanalytic variability was selected for discovery of lung cancer biomarkers. The impact of sample collection variation on these candidate markers was tested in the subset of samples with higher SMV scores so that the most robust markers could be used to create disease classifiers. The discovery sample set (n = 363) was from a multi-center study of 94 non-small cell lung cancer (NSCLC) cases and 269 long-term smokers and benign pulmonary nodule controls. The analysis resulted in a 7-marker panel with an AUC of 0.85 for all cases (68% adenocarcinoma, 32% squamous) and an AUC of 0.93 for squamous cell carcinoma in particular. This panel was validated by making blinded predictions in two independent cohorts (n = 138 in the first validation and n = 135 in the second). The model was recalibrated for a panel format prior to unblinding the second cohort. The AUCs overall were 0.81 and 0.77, and for squamous cell tumors alone were 0.89 and 0.87. The estimated negative predictive value for a 15% disease prevalence was 93% overall and 99% for squamous lung tumors. The proteins in the classifier function in destruction of the extracellular matrix, metabolic homeostasis and inflammation., Conclusions: Selecting biomarkers resistant to sample processing variation led to robust lung cancer biomarkers that performed consistently in independent validations. They form a sensitive signature for detection of lung cancer, especially squamous cell histology. This non-invasive test could be used to improve the positive predictive value of CT screening, with the potential to avoid invasive evaluation of nonmalignant pulmonary nodules.
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- 2014
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48. Erlotinib, erlotinib-sulindac versus placebo: a randomized, double-blind, placebo-controlled window trial in operable head and neck cancer.
- Author
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Gross ND, Bauman JE, Gooding WE, Denq W, Thomas SM, Wang L, Chiosea S, Hood BL, Flint MS, Sun M, Conrads TP, Ferris RL, Johnson JT, Kim S, Argiris A, Wirth L, Nikiforova MN, Siegfried JM, and Grandis JR
- Subjects
- Adult, Aged, Aged, 80 and over, Carcinoma, Squamous Cell metabolism, Carcinoma, Squamous Cell pathology, Cohort Studies, Double-Blind Method, Erlotinib Hydrochloride, Female, Follow-Up Studies, Head and Neck Neoplasms metabolism, Head and Neck Neoplasms pathology, Humans, Immunoenzyme Techniques, Male, Middle Aged, Neoplasm Staging, Prognosis, Quinazolines administration & dosage, Sulindac administration & dosage, Tissue Array Analysis, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Biomarkers, Tumor metabolism, Carcinoma, Squamous Cell drug therapy, ErbB Receptors antagonists & inhibitors, Head and Neck Neoplasms drug therapy
- Abstract
Purpose: The EGF receptor (EGFR) and COX2 pathways are upregulated in head and neck squamous cell carcinoma (HNSCC). Preclinical models indicate synergistic antitumor activity from dual blockade. We conducted a randomized, double-blind, placebo-controlled window trial of erlotinib, an EGFR inhibitor; erlotinib plus sulindac, a nonselective COX inhibitor; versus placebo., Experimental Design: Patients with untreated, operable stage II-IVb HNSCC were randomized 5:5:3 to erlotinib, erlotinib-sulindac, or placebo. Tumor specimens were collected before and after seven to 14 days of treatment. The primary endpoint was change in Ki67 proliferation index. We hypothesized an ordering effect in Ki67 reduction: erlotinib-sulindac > erlotinib > placebo. We evaluated tissue microarrays by immunohistochemistry for pharmacodynamic modulation of EGFR and COX2 signaling intermediates., Results: From 2005-2009, 47 patients were randomized for the target 39 evaluable patients. Thirty-four tumor pairs were of sufficient quality to assess biomarker modulation. Ki67 was significantly decreased by erlotinib or erlotinib-sulindac (omnibus comparison, two-sided Kruskal-Wallis, P = 0.04). Wilcoxon pairwise contrasts confirmed greater Ki67 effect in both erlotinib groups (erlotinib-sulindac vs. placebo, P = 0.043; erlotinib vs. placebo, P = 0.027). There was a significant trend in ordering of Ki67 reduction: erlotinib-sulindac > erlotinib > placebo (two-sided exact Jonckheere-Terpstra, P = 0.0185). Low baseline pSrc correlated with greater Ki67 reduction (R(2) = 0.312, P = 0.024)., Conclusions: Brief treatment with erlotinib significantly decreased proliferation in HNSCC, with additive effect from sulindac. Efficacy studies of dual EGFR-COX inhibition are justified. pSrc is a potential resistance biomarker for anti-EGFR therapy, and warrants investigation as a molecular target., (©2014 American Association for Cancer Research.)
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- 2014
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49. Pan-erbB inhibition potentiates BRAF inhibitors for melanoma treatment.
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Ng YK, Lee JY, Supko KM, Khan A, Torres SM, Berwick M, Ho J, Kirkwood JM, Siegfried JM, and Stabile LP
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- Apoptosis drug effects, Cell Line, Tumor, Cell Proliferation drug effects, Dose-Response Relationship, Drug, ErbB Receptors metabolism, G1 Phase Cell Cycle Checkpoints drug effects, Humans, Indoles pharmacology, Inhibitory Concentration 50, Ligands, Melanoma genetics, Melanoma pathology, Molecular Targeted Therapy, Morpholines pharmacology, Mutation, Proto-Oncogene Proteins B-raf genetics, Proto-Oncogene Proteins B-raf metabolism, Signal Transduction drug effects, Skin Neoplasms genetics, Skin Neoplasms pathology, Sulfonamides pharmacology, Vemurafenib, Antineoplastic Combined Chemotherapy Protocols pharmacology, ErbB Receptors antagonists & inhibitors, Melanoma enzymology, Protein Kinase Inhibitors pharmacology, Proto-Oncogene Proteins B-raf antagonists & inhibitors, Skin Neoplasms enzymology
- Abstract
The BRAF inhibitor vemurafenib is currently used for treating patients with BRAF V600E mutant melanoma. However, the responses to vemurafenib are generally partial and of relatively short duration. Recent evidence suggests that activation of the epidermal growth factor receptor (EGFR)/erbB signaling pathway may be responsible for the development of BRAF inhibitor resistance in melanoma patients. In this study, we characterized the erbB family of receptors and ligands in melanoma cell lines and examined whether targeting both BRAF and erbB provided enhanced antitumor activity in BRAF mutant melanoma. Variable levels of erbB2, erbB3, and truncated erbB4 were expressed in both BRAF wildtype and mutant melanoma cells with no significant differences between wildtype and mutant lines. EGFR was rarely expressed. Neuregulin 3 and neuregulin 4 were the major erbB ligands released by melanoma cells. Multi-erbB targeting with the irreversible tyrosine kinase inhibitor canertinib exerted a more effective growth inhibitory effect in both BRAF wildtype and mutant melanoma cells compared with the single-erbB or dual-erbB targeting inhibitors, gefitinib, erlotinib, and lapatinib. Canertinib inhibited both EGF-induced and neuregulin 1-induced erbB downstream signaling in both mutant and wildtype cell lines. However, canertinib induced apoptosis and sub-G1 arrest only in mutant cells. Canertinib statistically increased the antiproliferative effects of vemurafenib in the BRAF mutant melanoma cell lines while little or no enhanced effect was observed with the combination treatment in the wildtype cell lines. A combined inhibition strategy targeting BRAF together with multiple erbB family kinases is potentially beneficial for treating BRAF V600E mutant melanoma. Wildtype BRAF melanoma may also benefit from a multi-erbB kinase inhibitor.
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- 2014
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50. Estrongenic steroid hormones in lung cancer.
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Siegfried JM and Stabile LP
- Subjects
- Animals, Aromatase metabolism, Female, Humans, Lung Neoplasms diagnosis, Male, Receptors, Estrogen metabolism, Receptors, Progesterone metabolism, Estrogens metabolism, Gonadal Steroid Hormones metabolism, Lung Neoplasms etiology, Lung Neoplasms metabolism
- Abstract
It is becoming increasingly clear that steroid hormones are involved in the biology of many organs outside the reproductive system. Evidence has been accumulating since the mid 1990s that the lung contains receptors for both estrogen and progesterone and that these hormones have some role in lung development, pulmonary inflammation, and lung cancer. The estrogen receptor β (ERβ) is the major ER expressed in lung tissues, while inflammatory cells capable of infiltrating the lung are reported to express both ERα and ERβ. Although there is evidence in animals of preferential effects of ERβ in the lungs of females, human lung tumors from males also contain ERβ-positive cells and express aromatase, the enzyme that converts testosterone to estrogens. This review will discuss current literature findings on the role of the ERs and the progesterone receptor (PR), as well CYP19 (aromatase), the rate-limiting enzyme in the synthesis of estrogen, in lung cancer., (Copyright © 2014 Elsevier Inc. All rights reserved.)
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- 2014
- Full Text
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