12 results on '"Gay, C. M."'
Search Results
2. Determination of 1-benzo[b]thien-2-ylethanone and related impurities by high performance liquid chromatography
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Shada, D. M., Wong, C. F., Elrod, L., Morley, J. A., and Gay, C. M.
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- 1996
- Full Text
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3. Triple blockade of Ido-1, PD-L1 and MEK as a potential therapeutic strategy in NSCLC
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Carminia Maria Della Corte, Vincenza Ciaramella, Kavya Ramkumar, Giovanni Vicidomini, Alfonso Fiorelli, Valerio Nardone, Salvatore Cappabianca, Immacolata Cozzolino, Federica Zito Marino, Gaetano Di Guida, Qi Wang, Robert Cardnell, Carl Michael Gay, Davide Ciardiello, Erika Martinelli, Teresa Troiani, Giulia Martini, Stefania Napolitano, Jing Wang, Lauren Averett Byers, Fortunato Ciardiello, Floriana Morgillo, Della Corte, C. M., Ciaramella, V., Ramkumar, K., Vicidomini, G., Fiorelli, A., Nardone, V., Cappabianca, S., Cozzolino, I., Zito Marino, F., Di Guida, G., Wang, Q., Cardnell, R., Gay, C. M., Ciardiello, D., Martinelli, E., Troiani, T., Martini, G., Napolitano, S., Wang, J., Byers, L. A., Ciardiello, F., and Morgillo, F.
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Lung Neoplasms ,Resistance ,EMT ,Antibodies, Monoclonal ,Adenocarcinoma of Lung ,General Medicine ,Adenocarcinoma ,MAP Kinase Kinase Kinases ,Ido-1 ,General Biochemistry, Genetics and Molecular Biology ,B7-H1 Antigen ,Checkpoint inhibitor ,Carcinoma, Non-Small-Cell Lung ,Leukocytes, Mononuclear ,Tumor Microenvironment ,Humans ,Indoleamine-Pyrrole 2,3,-Dioxygenase ,Immune Checkpoint Inhibitors ,Protein Kinase Inhibitors - Abstract
Background Despite the recent progress in the treatment and outcome of Non Small Cell Lung Cancer (NSCLC), immunotherapy has still significant limitations reporting a significant proportion of patients not benefiting from therapy, even in patients with high PD-L1 expression. We have previously demonstrated that the combined inhibition of MEK and PD-L1 in NSCLC patients derived three dimensional cultures exerted significant synergistic effect in terms of immune-dependent cancer cell death. However, subsequent experiments analyzing the expression of Indoleamine 2,3-dioxygenase-1 (Ido-1) gene expression demonstrated that Ido-1 resulted unaffected by the MEK inhibition and even increased after the combined inhibition of MEK and PD-L1 thus representing a potential escape mechanism to this combination. Methods We analyzed transcriptomic profile of NSCLC lung adenocarcinoma cohort of TCGA (The Cancer Genome Atlas), stratifying tumors based on EMT (Epithelial mesenchymal Transition) score; in parallel, we investigated the activation of Ido-1 pathway and modulation of immune cytokines productions both in NSCLC cells lines, in peripheral blood mononuclear cells (PBMCs) and in ex-vivo NSCLC spheroids induced by triple inhibition with an anti-PD-L1 monoclonal antibody, the MEK inhibitor and the Ido-1 inhibitor. Results In NSCLC lung adenocarcinoma patient cohort (from TCGA) Ido-1 gene expression was significantly higher in samples classified as mesenchymal according EMT score. Similarly, on a selected panel of NSCLC cell lines higher expression of MEK and Ido-1 related genes was detected in cells with mesenchymal phenotype according EMT score, thus suggesting a potential correlation of co-activation of these two pathways in the context of EMT, with cancer cells sustaining an immune-suppressive microenvironment. While exerting an antitumor activity, the dual blockade of MEK and PD-L1 enhances the secretion of pro-inflammatory cytokines (IFNγ, TNFα, IL-12 and IL-6) and, consequently, the expression of new immune checkpoints such as Ido-1. The triple inhibition with an anti-PD-L1 monoclonal antibody, the MEK inhibitor and the Ido-1 inhibitor demonstrated significant antiproliferative and proapoptotic activity on ex-vivo NSCLC samples; at the same time the triple combination kept increased the levels of pro-inflammatory cytokines produced by both PBMCs and tumor spheroids in order to sustain the immune response and simultaneously decreased the expression of other checkpoint (such as CTLA-4, Ido-1 and TIM-3) thus promoting an immune-reactive and inflamed micro-environment. Conclusions We show that Ido-1 activation is a possible escape mechanism to immune-mediated cell death induced by combination of PD-L1 and MEK inhibitors: also, we show that triple combination of anti-PD-L1, anti-MEK and anti-Ido-1 drugs may overcome this negative feedback and restore anti-tumor immune response in NSCLC patients’ derived three dimensional cultures.
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- 2022
4. Combination Treatment of the Oral CHK1 Inhibitor, SRA737, and Low-Dose Gemcitabine Enhances the Effect of Programmed Death Ligand 1 Blockade by Modulating the Immune Microenvironment in SCLC
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Triparna Sen, Carminia M. Della Corte, Snezana Milutinovic, Robert J. Cardnell, Lixia Diao, Kavya Ramkumar, Carl M. Gay, C. Allison Stewart, Youhong Fan, Li Shen, Ryan J. Hansen, Bryan Strouse, Michael P. Hedrick, Christian A. Hassig, John V. Heymach, Jing Wang, Lauren A. Byers, Sen, T., Della Corte, C. M., Milutinovic, S., Cardnell, R. J., Diao, L., Ramkumar, K., Gay, C. M., Stewart, C. A., Fan, Y., Shen, L., Hansen, R. J., Strouse, B., Hedrick, M. P., Hassig, C. A., Heymach, J. V., Wang, J., and Byers, L. A.
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0301 basic medicine ,Pulmonary and Respiratory Medicine ,Lung Neoplasms ,medicine.medical_treatment ,Programmed Cell Death 1 Receptor ,Administration, Oral ,DNA damage response ,Heterocyclic Compounds, 4 or More Rings ,Deoxycytidine ,Article ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Cancer immunotherapy ,Heterocyclic Compounds, 4 or More Ring ,Tumor Microenvironment ,medicine ,Animals ,Humans ,Cytotoxic T cell ,Chemotherapy ,Animal ,business.industry ,SCLC ,Immunotherapy ,Low-dose gemcitabine ,Gemcitabine ,Combined Modality Therapy ,Small Cell Lung Carcinoma ,Xenograft Model Antitumor Assays ,Immune checkpoint ,respiratory tract diseases ,Blockade ,Lung Neoplasm ,Regimen ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Cancer research ,Female ,business ,Immune checkpoint blockade ,Human ,medicine.drug - Abstract
Introduction Despite the enthusiasm surrounding cancer immunotherapy, most SCLC patients show very modest response to immune checkpoint inhibitor monotherapy treatment. Therefore, there is growing interest in combining immune checkpoint blockade with chemotherapy and other treatments to enhance immune checkpoint blockade efficacy. Based on favorable clinical trial results, chemotherapy and immunotherapy combinations have been recently approved by the U.S. Food and Drug Administration for frontline treatment for SCLC. Methods and Results Here, we show that combined treatment of SRA737, an oral CHK1 inhibitor, and anti–programmed death ligand 1 (PD-L1) leads to an antitumor response in multiple cancer models, including SCLC. We further show that combining low, non-cytotoxic doses of gemcitabine with SRA737 + anti–PD-L1/anti–PD-1 significantly increased antitumorigenic CD8+ cytotoxic T cells, dendritic cells, and M1 macrophage populations in an SCLC model. This regimen also led to a significant decrease in immunosuppressive M2 macrophage and myeloid-derived suppressor cell populations, as well as an increase in the expression of the type I interferon beta 1 gene, IFNβ, and chemokines, CCL5 and CXCL10. Conclusions Given that anti–PD-L1/anti–PD-1 drugs have recently been approved as monotherapy and in combination with chemotherapy for the treatment of SCLC, and that the SRA737 + low dose gemcitabine regimen is currently in clinical trials for SCLC and other malignancies, our preclinical data provide a strong rational for combining this regimen with inhibitors of the PD-L1/PD-1 pathway.
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- 2019
5. Lung cancer models reveal SARS-CoV-2-induced EMT contributes to COVID-19 pathophysiology
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C. Allison Stewart, Carl M. Gay, Kavya Ramkumar, Kasey R. Cargill, Robert J. Cardnell, Monique B. Nilsson, Simon Heeke, Elizabeth M. Park, Samrat T. Kundu, Lixia Diao, Qi Wang, Li Shen, Yuanxin Xi, Bingnan Zhang, Carminia Maria Della Corte, Youhong Fan, Kiran Kundu, Boning Gao, Kimberley Avila, Curtis R. Pickering, Faye M. Johnson, Jianjun Zhang, Humam Kadara, John D. Minna, Don L. Gibbons, Jing Wang, John V. Heymach, Lauren Averett Byers, Stewart, C. A., Gay, C. M., Ramkumar, K., Cargill, K. R., Cardnell, R. J., Nilsson, M. B., Heeke, S., Park, E. M., Kundu, S. T., Diao, L., Wang, Q., Shen, L., Xi, Y., Zhang, B., Della Corte, C. M., Fan, Y., Kundu, K., Gao, B., Avila, K., Pickering, C. R., Johnson, F. M., Zhang, J., Kadara, H., Minna, J. D., Gibbons, D. L., Wang, J., Heymach, J. V., and Byers, L. A.
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Pulmonary and Respiratory Medicine ,Oncology ,medicine.medical_specialty ,Lung Neoplasms ,Coronavirus disease 2019 (COVID-19) ,viruses ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Population ,ACE2 ,Bronchi ,Peptidyl-Dipeptidase A ,NSCLC ,Pathogenesis ,Internal medicine ,medicine ,Humans ,ZEB1 ,Epithelial–mesenchymal transition ,Respiratory system ,education ,Lung cancer ,Lung ,Psychological repression ,Cell entry ,education.field_of_study ,SARS-CoV-2 ,business.industry ,Mesenchymal stem cell ,EMT ,AXL ,COVID-19 ,Cancer ,medicine.disease ,Editorial ,medicine.anatomical_structure ,Viral Receptor ,Cancer research ,Original Article ,business ,Bristol-Myers ,Human - Abstract
Background: SARS-CoV-2 infection is the cause of the respiratory illness COVID-19, which presents most frequently with respiratory symptoms SARS-CoV-2 cell entry requires interactions with ACE2 and TMPRSS2 on the surface of the host cell Cancer patients and, specifically, those with thoracic malignancies seem to experience poorer clinical outcomes Methods: We utilized bulk and single-cell transcriptional data from a combination of normal and malignant tissues and cells from aerodigestive and respiratory tracts to explore mechanisms governing the expression of ACE2 and TMPRSS2 Additionally, we determined the effect of EMT induction, ZEB1 modulation, and SARS-CoV-2 infection on ACE2 expression Results: Our bulk data suggests that aerodigestive and lung cancer models express a broad range of ACE2 and TMRPSS2, particularly in epithelial cells, and would serve as good models for studying SARS-CoV-2 infection We assessed the relationship between ACE2 and epithelial differentiation in numerous datasets, and found consistent positive correlations with transcriptional and microRNA signifiers of epithelial differentiation The miR-200 family – zinc finger E-box-binding homeobox 1 (ZEB1) pathway, which is an established regulator of EMT, also directly regulates ACE2 expression, likely via putative ZEB1 repressor sites located in the ACE2 promoter Furthermore, SARS-CoV-2 infection reduces ACE2 expression and shifts cells to a more mesenchymal phenotype with loss of EPCAM and upregulation of ZEB1 and other EMT-associated genes Conclusions: ACE2-positive cells are almost exclusively epithelial and unexpectedly rare, considering the devastating impact of this infection Following viral entry, SARS-CoV-2 infection induces molecular changes within the cells that are reminiscent of EMT, including increased ZEB1 ZEB1, in turn, appears to directly repress the expression of ACE2 This SARS-CoV-2-induced ACE2 deficiency, compounded by the downregulation of genes, including claudins, which play a critical role in restricting epithelial and endothelial permeability, exposes respiratory cells to increased risk of edema and acute respiratory distress syndrome (ARDS) Legal entity responsible for the study: The authors Funding: NIH/NCI R01-CA207295 (L A B ), NIH/NCI U01-CA213273 (L A B , J V H ), CCSG P30-CA01667 (L A B ), University of Texas SPORE in Lung Cancer P5-CA070907 (L A B , D L G , J V H , C M G ), the Department of Defense (LC170171;L A B ), Khalifa Bin Zayed Al Nahyan Foundation (C M G ), RP170067 (EMP), through generous philanthropic contributions to The University of Texas MD Anderson Lung Cancer Moon Shot Program and Andrew Sabin Family Fellowship, and The Rexanna Foundation for Fighting Lung Cancer Disclosure: C Gay: Research grant/Funding (self): Astra Zeneca J V Heymach: Advisory/Consultancy: AstraZeneca;Advisory/Consultancy: Boehringer Ingelheim;Advisory/Consultancy: Exelixis;Advisory/Consultancy: Genentech;Advisory/Consultancy: GlaxoSmithKline;Advisory/Consultancy: Guardant Health;Advisory/Consultancy: Hengrui;Advisory/Consultancy: Spectrum L A Byers: Advisory/Consultancy, Research grant/Funding (self): AstraZeneca;Advisory/Consultancy, Research grant/Funding (self): AbbVie;Advisory/Consultancy, Research grant/Funding (self): GenMab;Advisory/Consultancy: BergenBio;Advisory/Consultancy: Pharma Mar SA;Advisory/Consultancy, Research grant/Funding (self): Sierra Oncology;Advisory/Consultancy: Merck;Advisory/Consultancy: Bristol Myers Squibb;Advisory/Consultancy: Genentech;Advisory/Consultancy: Pfizer;Research grant/Funding (self): Tolero Pharmaceuticals All other authors have declared no conflicts of interest
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- 2021
6. Patterns of transcription factor programs and immune pathway activation define four major subtypes of SCLC with distinct therapeutic vulnerabilities
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Carl M. Gay, C. Allison Stewart, Elizabeth M. Park, Lixia Diao, Sarah M. Groves, Simon Heeke, Barzin Y. Nabet, Junya Fujimoto, Luisa M. Solis, Wei Lu, Yuanxin Xi, Robert J. Cardnell, Qi Wang, Giulia Fabbri, Kasey R. Cargill, Natalie I. Vokes, Kavya Ramkumar, Bingnan Zhang, Carminia M. Della Corte, Paul Robson, Stephen G. Swisher, Jack A. Roth, Bonnie S. Glisson, David S. Shames, Ignacio I. Wistuba, Jing Wang, Vito Quaranta, John Minna, John V. Heymach, Lauren Averett Byers, Gay, C. M., Stewart, C. A., Park, E. M., Diao, L., Groves, S. M., Heeke, S., Nabet, B. Y., Fujimoto, J., Solis, L. M., Lu, W., Xi, Y., Cardnell, R. J., Wang, Q., Fabbri, G., Cargill, K. R., Vokes, N. I., Ramkumar, K., Zhang, B., Della Corte, C. M., Robson, P., Swisher, S. G., Roth, J. A., Glisson, B. S., Shames, D. S., Wistuba, I. I., Wang, J., Quaranta, V., Minna, J., Heymach, J. V., and Byers, L. A.
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0301 basic medicine ,Cancer Research ,Lung Neoplasms ,Prognosi ,medicine.medical_treatment ,Mice, Nude ,Biology ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Cell Line, Tumor ,medicine ,Animals ,Humans ,neuroendocrine ,neoplasms ,Transcription factor ,Cisplatin ,Kinase ,Animal ,ASCL1 ,EMT ,Immunity ,SCLC ,POU2F3 ,Immunotherapy ,Gene signature ,Prognosis ,Small Cell Lung Carcinoma ,humanities ,respiratory tract diseases ,Gene Expression Regulation, Neoplastic ,Lung Neoplasm ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,NEUROD1 ,intratumoral heterogeneity ,Cancer research ,Female ,medicine.drug ,Human ,Transcription Factors - Abstract
Despite molecular and clinical heterogeneity, small cell lung cancer (SCLC) is treated as a single entity with predictably poor results. Using tumor expression data and non-negative matrix factorization, we identify four SCLC subtypes defined largely by differential expression of transcription factors ASCL1, NEUROD1, and POU2F3 or low expression of all three transcription factor signatures accompanied by an Inflamed gene signature (SCLC-A, N, P, and I, respectively). SCLC-I experiences the greatest benefit from the addition of immunotherapy to chemotherapy, while the other subtypes each have distinct vulnerabilities, including to inhibitors of PARP, Aurora kinases, or BCL-2. Cisplatin treatment of SCLC-A patient-derived xenografts induces intratumoral shifts toward SCLC-I, supporting subtype switching as a mechanism of acquired platinum resistance. We propose that matching baseline tumor subtype to therapy, as well as manipulating subtype switching on therapy, may enhance depth and duration of response for SCLC patients. Gay et al. provide a classification for four subtypes of small cell lung cancer, each with unique molecular features and therapeutic vulnerabilities. An inflamed, mesenchymal subtype predicts benefit with the addition of immunotherapy to chemotherapy. Intratumoral switching between chemosensitive and chemoresistant subtypes accompanies therapeutic resistance.
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- 2021
7. AXL inhibition induces DNA damage and replication stress in non-small cell lung cancer cells and promotes sensitivity to ATR inhibitors
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Kavya Ramkumar, C. Allison Stewart, Kasey R. Cargill, Carminia M. Della Corte, Qi Wang, Li Shen, Lixia Diao, Robert J. Cardnell, David H. Peng, B. Leticia Rodriguez, You-Hong Fan, John V. Heymach, Jing Wang, Carl M. Gay, Don L. Gibbons, Lauren A. Byers, Ramkumar, K., Stewart, C. A., Cargill, K. R., della Corte, C. M., Wang, Q., Shen, L., Diao, L., Cardnell, R. J., Peng, D. H., Rodriguez, B. L., Fan, Y. -H., Heymach, J. V., Wang, J., Gay, C. M., Gibbons, D. L., and Byers, L. A.
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0301 basic medicine ,Cancer Research ,Lung Neoplasms ,DNA damage ,Protein Kinase Inhibitor ,Apoptosis ,Receptor tyrosine kinase ,Article ,03 medical and health sciences ,0302 clinical medicine ,Carcinoma, Non-Small-Cell Lung ,Cell Line, Tumor ,Proto-Oncogene Proteins ,Humans ,Molecular Biology ,Mitotic catastrophe ,Protein Kinase Inhibitors ,Proto-Oncogene Protein ,biology ,Cell growth ,Chemistry ,Apoptosi ,Receptor Protein-Tyrosine Kinases ,MERTK ,Axl Receptor Tyrosine Kinase ,Lung Neoplasm ,Wee1 ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,PARP inhibitor ,biology.protein ,Cancer research ,TYRO3 ,Human ,DNA Damage - Abstract
AXL, a TAM (TYRO3, AXL, and MERTK) family receptor tyrosine kinase, is increasingly being recognized as a key determinant of resistance to targeted therapies, as well as chemotherapy and radiation in non–small cell lung cancer (NSCLC) and other cancers. We further show here that high levels of AXL and epithelial-to-mesenchymal transition were frequently expressed in subsets of both treatment-naïve and treatment-relapsed NSCLC. Previously, we and others have demonstrated a role for AXL in mediating DNA damage response (DDR), as well as resistance to inhibition of WEE1, a replication stress response kinase. Here, we show that BGB324 (bemcentinib), a selective small-molecule AXL inhibitor, caused DNA damage and induced replication stress, indicated by ATR/CHK1 phosphorylation, more significantly in TP53-deficient NSCLC cell lines. Similar effects were also observed in large-cell neuroendocrine carcinoma (LCNEC) cell lines. High AXL protein levels were also associated with resistance to ATR inhibition. Combined inhibition of AXL and ATR significantly decreased cell proliferation of NSCLC and LCNEC cell lines. Mechanistically, combined inhibition of AXL and ATR significantly increased RPA32 hyperphosphorylation and DNA double-strand breaks and induced markers of mitotic catastrophe. Notably, NSCLC cell lines with low levels of SLFN11, a known predictive biomarker for platinum and PARP inhibitor sensitivity, were more sensitive to AXL/ATR cotargeting. These findings demonstrate a novel and unexpected role for AXL in replication stress tolerance, with potential therapeutic implications. Implications: These findings demonstrate that the combination of AXL and ATR inhibitors could be a promising therapeutic combination for NSCLC, LCNEC, and other cancers.
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- 2020
8. Beyond chemotherapy: Emerging biomarkers and therapies as small cell lung cancer enters the immune checkpoint era
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Carminia M. Della Corte, Carl M. Gay, Lauren A. Byers, Della Corte, C. M., Gay, C. M., and Byers, L. A.
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Cancer Research ,Chemotherapy ,Lung Neoplasms ,business.industry ,Patient Selection ,medicine.medical_treatment ,Small Cell Lung Carcinoma ,Article ,Immune checkpoint ,Oncology ,Biomarkers, Tumor ,Cancer research ,Humans ,Medicine ,Immunotherapy ,Molecular Targeted Therapy ,Non small cell ,business - Abstract
For decades, clinicians have witnessed no therapeutic advances for small cell lung cancer, including no US Food and Drug Administration-approved targeted therapies; recently, immune-checkpoint blockade has emerged as a promising new option for the treatment of patients with relapsed small cell lung cancer (including recent US Food and Drug Administration approval of nivolumab in the third-line setting) and soon may represent the frontline standard of care in combination with chemotherapy. However, there is a need to uncover biomarkers to guide patient selection and develop novel approaches to enhance response to immunotherapies.
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- 2019
9. STING Pathway Expression Identifies NSCLC With an Immune-Responsive Phenotype
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Lixia Diao, Youhong Fan, Marcelo V. Negrao, David H. Peng, Triparna Sen, John V. Heymach, Vassiliki A. Papadimitrakopoulou, Robert J. Cardnell, Ignacio I. Wistuba, Junya Fujimoto, C. Allison Stewart, Laura A. Gibson, Carminia Maria Della Corte, Bertha Leticia Rodriguez, Carmen Behrens, Jing Wang, Kavya Ramkumar, Jared J. Fradette, Qi Wang, Lauren Averett Byers, Luisa M. Solis Soto, Ferdinandos Skoulidis, Don L. Gibbons, Della Corte, C. M., Sen, T., Gay, C. M., Ramkumar, K., Diao, L., Cardnell, R. J., Rodriguez, B. L., Stewart, C. A., Papadimitrakopoulou, V. A., Gibson, L., Fradette, J. J., Wang, Q., Fan, Y., Peng, D. H., Negrao, M. V., Wistuba, I. I., Fujimoto, J., Solis Soto, L. M., Behrens, C., Skoulidis, F., Heymach, J. V., Wang, J., Gibbons, D. L., and Byers, L. A.
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0301 basic medicine ,Pulmonary and Respiratory Medicine ,Proteomics ,Lung Neoplasms ,medicine.medical_treatment ,CCL5 ,Article ,B7-H1 Antigen ,Targeted therapy ,Bites and Sting ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Chemoimmunotherapy ,Carcinoma, Non-Small-Cell Lung ,medicine ,Tumor Microenvironment ,CXCL10 ,Humans ,Bites and Stings ,Lung cancer ,Innate immunity ,business.industry ,Proteomic ,Immunotherapy ,medicine.disease ,eye diseases ,Sting ,030104 developmental biology ,Phenotype ,Oncology ,030220 oncology & carcinogenesis ,Cancer research ,Immune checkpoint ,business ,STING ,Human - Abstract
Introduction Although the combination of anti–programmed cell death-1 or anti–programmed cell death ligand-1 (PD-L1) with platinum chemotherapy is a standard of care for NSCLC, clinical responses vary. Even though predictive biomarkers (which include PD-L1 expression, tumor mutational burden, and inflamed immune microenvironment) are validated for immunotherapy, their relevance to chemoimmunotherapy combinations is less clear. We have recently reported that activation of the stimulator of interferon genes (STING) innate immune pathway enhances immunotherapy response in SCLC. Here, we hypothesize that STING pathway activation may predict and underlie predictive correlates of antitumor immunity in NSCLC. Methods We analyzed transcriptomic and proteomic profiles in two NSCLC cohorts from our institution (treatment-naive patients in the Profiling of Resistance Patterns and Oncogenic Signaling Pathways in Evaluation of Cancers of the Thorax study and relapsed patients in the Biomarker-Integrated Approaches of Targeted Therapy for Lung Cancer Elimination study) and The Cancer Genome Atlas (N = 1320). Tumors were stratified by STING activation on the basis of protein or mRNA expression of cyclic GMP-AMP synthase, phospho-STING, and STING-mediated chemokines (chemokine ligand 5 [CCL5] and C-X-C motif chemokine 10 [CXCL10]). STING activation in patient tumors and in platinum-treated preclinical NSCLC models was correlated with biomarkers of immunotherapy response. Results STING activation is associated with higher levels of intrinsic DNA damage, targetable immune checkpoints, and chemokines in treatment-naive and relapsed lung adenocarcinoma. We observed that tumors with lower STING and immune gene expression show higher frequency of serine-threonine kinase 11 (STK11) mutations; however, we identified a subset of these tumors that are TP53 comutated and display high immune- and STING-related gene expression. Treatment with cisplatin increases STING pathway activation and PD-L1 expression in multiple NSCLC preclinical models, including adeno- and squamous cell carcinoma. Conclusions STING pathway activation in NSCLC predicts features of immunotherapy response and is enhanced by cisplatin treatment. This suggests a possible predictive biomarker and mechanism for improved response to chemoimmunotherapy combinations.
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- 2019
10. ILK and SHP2 expression identify a poor prognostic cohort of EGFR-mutant lung cancer
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Carminia Maria Della Corte, Carl Michael Gay, Lauren Averett Byers, Floriana Morgillo, Della Corte, C. M., Gay, C. M., Byers, L. A., and Morgillo, F.
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Male ,Research paper ,Signaling pathways ,Lung Neoplasms ,MAP Kinase Signaling System ,Prognosi ,Mutant ,MEDLINE ,Protein Tyrosine Phosphatase, Non-Receptor Type 11 ,Protein Serine-Threonine Kinases ,NSCLC ,General Biochemistry, Genetics and Molecular Biology ,Cohort Studies ,ErbB Receptors ,Text mining ,Src homology 2 domain-containing phosphatase 2 ,Carcinoma, Non-Small-Cell Lung ,Carcinoma ,Medicine ,Humans ,Integrin-linked kinase ,ErbB Receptor ,Lung cancer ,Protein Kinase Inhibitors ,Aged ,Hepatocyte Growth Factor ,Interleukin-6 ,business.industry ,General Medicine ,medicine.disease ,Prognosis ,EGFR mutations ,Progression-Free Survival ,Up-Regulation ,Gene Expression Regulation, Neoplastic ,Mutation ,Cohort ,Commentary ,Cancer research ,Regression Analysis ,Female ,Cohort Studie ,business ,Cohort study ,Human - Abstract
Background The activation of multiple signaling pathways jeopardizes the clinical efficacy of EGFR tyrosine kinase inhibitors (TKIs) in EGFR-mutation positive non-small cell lung cancer (NSCLC). Integrin-linked kinase (ILK) regulates the interactions between tumor cells and extracellular environment to activate signaling pathways and promote cell proliferation, migration, and epithelial-mesenchymal transition. Src homology 2 domain-containing phosphatase 2 (SHP2) is essential for receptor tyrosine kinase signaling and mitogen-activated protein kinase (MAPK) pathway activation. Methods We analyzed tumor ILK, β-receptor subunit glycoprotein 130 (gp130), SHP2, and stromal hepatocyte growth factor (HGF) and interleukin-6 (IL-6) mRNA expression in baseline tumor specimens of advanced EGFR-mutation positive NSCLC patients treated with EGFR TKIs. Results ILK, when highly expressed, was an independent poor prognostic factor for the progression-free survival of the patients, both in the univariate (hazard ratio [HR for disease progression, 2.49; 95% CI, 1.37–4.52; P = .0020]) and in the multivariate (HR 3.74; 95% CI, 1.33–10.56; P = .0126) Cox regression model. Patients with high SHP2 expression had an almost 13-month shorter progression-free survival (P = .0094) and an 18-month shorter overall survival (P = .0182) in comparison to those with low SHP2 mRNA expression. Interpretation The levels of ILK and SHP2 could be predictive for upfront combinatory therapy of EGFR TKIs plus SHP2 or ILK inhibitors. Fund A grant from La Caixa Foundation, an Instituto de Salud Carlos III grant (RESPONSE, PIE16/00011), an Instituto de Salud Carlos III grant (PI14/01678), a Marie Skłodowska-Curie Innovative Training Networks European Grant (ELBA No 765492) and a Spanish Association Against Cancer (AECC) grant (PROYE18012ROSE).
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- 2019
11. Agenda for action.
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Gay CM
- Subjects
- United States, Physicians, Women, Societies, Medical
- Published
- 1977
12. Influence of Concomitant Pratylenchus brachyurus and Meloidogyne spp. on Root Penetration and Population Dynamics.
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Gay CM and Bird GW
- Abstract
Populations of Pratylenchus brachyurus on cotton were increased significantly in the presence of either Meloidogyne incognita or M. arenaria.This occurred with either simultaneous inoculation or prior invasion by M. incognita. P. brachyurus penetrated cotton roots previously invaded by, or simultaneously inoculated with, M. incognita, as well as, or better than, in the absence of M. incognita. Prior invasion by M. incognita, however, suppressed P. brachyurus populations on tomato, while it had no effect on alfalfa and tobacco. Populations of M. incognita on cotton were generally inhibited by the presence of P. brachyurus. Simultaneous inoculation with, or previous invasion by, P. brachyurus also inhibited root penetration by M. incognita. These findings emphasize the importance of host susceptibility in the study of concomitant nematode populations.
- Published
- 1973
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