26 results on '"Eleni Papadopoulos"'
Search Results
2. Data from Targeting HER2 Exon 20 Insertion–Mutant Lung Adenocarcinoma with a Novel Tyrosine Kinase Inhibitor Mobocertinib
- Author
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Kwok-Kin Wong, Sylvie Vincent, Rachael Brake, Victor M. Rivera, Haiquan Chen, Francois Gonzalvez, Sittinon Tang, Eleni Papadopoulos, Cassandra Thakurdin, Val Pyon, Hai Hu, Hailin Ding, Yuanwang Pan, Hua Zhang, Fei Li, Theresa E. Baker, Zhendong Gao, Jiehui Deng, David Peng, Jiansheng Wu, Johara Chouitar, Shougen Cao, Kwan Ho Tang, Chengwei Peng, Shengwu Liu, Michael Fitzgerald, Ting Chen, Shuai Li, and Han Han
- Abstract
No targeted treatments are currently approved for HER2 exon 20 insertion–mutant lung adenocarcinoma patients. Mobocertinib (TAK-788) is a potent irreversible tyrosine kinase inhibitor (TKI) designed to target human epidermal growth factor receptor 2 (HER2/ERBB2) exon 20 insertion mutations. However, the function of mobocertinib on HER2 exon 20 insertion–mutant lung cancer is still unclear. Here we conducted systematic characterization of preclinical models to understand the activity profile of mobocertinib against HER2 exon 20 insertions. In HER2 exon 20 insertion–mutant cell lines, the IC50 of mobocertinib was higher than poziotinib and comparable with or slightly lower than afatinib, neratinib, and pyrotinib. Mobocertinib had the lowest HER2 exon 20 insertion IC50/wild-type (WT) EGFR IC50 ratio, indicating that mobocertinib displayed the best selectivity profile in these models. Also, mobocertinib showed strong inhibitory activity in HER2 exon 20YVMA allograft and patient-derived xenograft models. In genetically engineered mouse models, HER2 exon 20G776>VC lung tumors exhibited a sustained complete response to mobocertinib, whereas HER2 exon 20YVMA tumors showed only partial and transient response. Combined treatment with a second antibody–drug conjugate (ADC) against HER2, ado-trastuzumab emtansine (T-DM1), synergized with mobocertinib in HER2 exon 20YVMA tumors. In addition to the tumor cell autonomous effect, sustained tumor growth control derived from M1 macrophage infiltration and CD4+ T-cell activation. These findings support the ongoing clinical development of mobocertinib (NCT02716116) and provide a rationale for future clinical evaluation of T-DM1 combinational therapy in HER2 exon 20YVMA insertion–mutant lung adenocarcinoma patients.Significance:This study elucidates the potent inhibitory activity of mobocertinib against HER2 exon 20 insertion–mutant lung cancer and the synergic effect of combined mobocertinib and T-DM1, providing a strong rationale for clinical investigation.
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- 2023
- Full Text
- View/download PDF
3. Table S1 from Targeting HER2 Exon 20 Insertion–Mutant Lung Adenocarcinoma with a Novel Tyrosine Kinase Inhibitor Mobocertinib
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Kwok-Kin Wong, Sylvie Vincent, Rachael Brake, Victor M. Rivera, Haiquan Chen, Francois Gonzalvez, Sittinon Tang, Eleni Papadopoulos, Cassandra Thakurdin, Val Pyon, Hai Hu, Hailin Ding, Yuanwang Pan, Hua Zhang, Fei Li, Theresa E. Baker, Zhendong Gao, Jiehui Deng, David Peng, Jiansheng Wu, Johara Chouitar, Shougen Cao, Kwan Ho Tang, Chengwei Peng, Shengwu Liu, Michael Fitzgerald, Ting Chen, Shuai Li, and Han Han
- Abstract
GSEA analysis of mobocertinib acquired resistant tumors versus response tumors Genes involved in "G2M CHECKPOINT", "MITOTIC SPINDLE" and "MTORC1 SIGNALING" pathways of HALLMARK gene sets.
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- 2023
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4. Figure S1 from Targeting HER2 Exon 20 Insertion–Mutant Lung Adenocarcinoma with a Novel Tyrosine Kinase Inhibitor Mobocertinib
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Kwok-Kin Wong, Sylvie Vincent, Rachael Brake, Victor M. Rivera, Haiquan Chen, Francois Gonzalvez, Sittinon Tang, Eleni Papadopoulos, Cassandra Thakurdin, Val Pyon, Hai Hu, Hailin Ding, Yuanwang Pan, Hua Zhang, Fei Li, Theresa E. Baker, Zhendong Gao, Jiehui Deng, David Peng, Jiansheng Wu, Johara Chouitar, Shougen Cao, Kwan Ho Tang, Chengwei Peng, Shengwu Liu, Michael Fitzgerald, Ting Chen, Shuai Li, and Han Han
- Abstract
Figure S1
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- 2023
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5. Figure S2 from Targeting HER2 Exon 20 Insertion–Mutant Lung Adenocarcinoma with a Novel Tyrosine Kinase Inhibitor Mobocertinib
- Author
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Kwok-Kin Wong, Sylvie Vincent, Rachael Brake, Victor M. Rivera, Haiquan Chen, Francois Gonzalvez, Sittinon Tang, Eleni Papadopoulos, Cassandra Thakurdin, Val Pyon, Hai Hu, Hailin Ding, Yuanwang Pan, Hua Zhang, Fei Li, Theresa E. Baker, Zhendong Gao, Jiehui Deng, David Peng, Jiansheng Wu, Johara Chouitar, Shougen Cao, Kwan Ho Tang, Chengwei Peng, Shengwu Liu, Michael Fitzgerald, Ting Chen, Shuai Li, and Han Han
- Abstract
Figure S2
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- 2023
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6. Figure S3 from Targeting HER2 Exon 20 Insertion–Mutant Lung Adenocarcinoma with a Novel Tyrosine Kinase Inhibitor Mobocertinib
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Kwok-Kin Wong, Sylvie Vincent, Rachael Brake, Victor M. Rivera, Haiquan Chen, Francois Gonzalvez, Sittinon Tang, Eleni Papadopoulos, Cassandra Thakurdin, Val Pyon, Hai Hu, Hailin Ding, Yuanwang Pan, Hua Zhang, Fei Li, Theresa E. Baker, Zhendong Gao, Jiehui Deng, David Peng, Jiansheng Wu, Johara Chouitar, Shougen Cao, Kwan Ho Tang, Chengwei Peng, Shengwu Liu, Michael Fitzgerald, Ting Chen, Shuai Li, and Han Han
- Abstract
Figure S3
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- 2023
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7. Figure S4 from Targeting HER2 Exon 20 Insertion–Mutant Lung Adenocarcinoma with a Novel Tyrosine Kinase Inhibitor Mobocertinib
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Kwok-Kin Wong, Sylvie Vincent, Rachael Brake, Victor M. Rivera, Haiquan Chen, Francois Gonzalvez, Sittinon Tang, Eleni Papadopoulos, Cassandra Thakurdin, Val Pyon, Hai Hu, Hailin Ding, Yuanwang Pan, Hua Zhang, Fei Li, Theresa E. Baker, Zhendong Gao, Jiehui Deng, David Peng, Jiansheng Wu, Johara Chouitar, Shougen Cao, Kwan Ho Tang, Chengwei Peng, Shengwu Liu, Michael Fitzgerald, Ting Chen, Shuai Li, and Han Han
- Abstract
Figure S4
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- 2023
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8. Table S4 from Generation of Genetically Engineered Mouse Lung Organoid Models for Squamous Cell Lung Cancers Allows for the Study of Combinatorial Immunotherapy
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Kwok-Kin Wong, Adam J. Bass, Cassandra Thakurdin, Ming-Sound Tsao, Christine Ng, Lynette M. Sholl, Joshua D. Campbell, Jiehui Deng, Patrick H. Lizotte, Heather Silver, Roderick T. Bronson, Jie Bin Liu, Yuanwang Pan, Val Pyon, Catríona M. Dowling, Eleni Papadopoulos, Ting Chen, Zhong Wu, Jin Zhou, Hua Zhang, and Josephine Hai
- Abstract
qRT-PCR primer sequences
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- 2023
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9. Data from Generation of Genetically Engineered Mouse Lung Organoid Models for Squamous Cell Lung Cancers Allows for the Study of Combinatorial Immunotherapy
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Kwok-Kin Wong, Adam J. Bass, Cassandra Thakurdin, Ming-Sound Tsao, Christine Ng, Lynette M. Sholl, Joshua D. Campbell, Jiehui Deng, Patrick H. Lizotte, Heather Silver, Roderick T. Bronson, Jie Bin Liu, Yuanwang Pan, Val Pyon, Catríona M. Dowling, Eleni Papadopoulos, Ting Chen, Zhong Wu, Jin Zhou, Hua Zhang, and Josephine Hai
- Abstract
Purpose:Lung squamous cell carcinoma (LSCC) is a deadly disease for which only a subset of patients responds to immune checkpoint blockade (ICB) therapy. Therefore, preclinical mouse models that recapitulate the complex genetic profile found in patients are urgently needed.Experimental Design:We used CRISPR genome editing to delete multiple tumor suppressors in lung organoids derived from Cre-dependent SOX2 knock-in mice. We investigated both the therapeutic efficacy and immunologic effects accompanying combination PD-1 blockade and WEE1 inhibition in both mouse models and LSCC patient-derived cell lines.Results:We show that multiplex gene editing of mouse lung organoids using the CRISPR–Cas9 system allows for efficient and rapid means to generate LSCCs that closely mimic the human disease at the genomic and phenotypic level. Using this genetically defined mouse model and three-dimensional tumoroid culture system, we show that WEE1 inhibition induces DNA damage that primes the endogenous type I IFN and antigen presentation system in primary LSCC tumor cells. These events promote cytotoxic T-cell–mediated clearance of tumor cells and reduce the accumulation of tumor-infiltrating neutrophils. Beneficial immunologic features of WEE1 inhibition are further enhanced by the addition of anti–PD-1 therapy.Conclusions:We developed a mouse model system to investigate a novel combinatory approach that illuminates a clinical path hypothesis for combining ICB with DNA damage–inducing therapies in the treatment of LSCC.
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- 2023
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- View/download PDF
10. Table S2 from Generation of Genetically Engineered Mouse Lung Organoid Models for Squamous Cell Lung Cancers Allows for the Study of Combinatorial Immunotherapy
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Kwok-Kin Wong, Adam J. Bass, Cassandra Thakurdin, Ming-Sound Tsao, Christine Ng, Lynette M. Sholl, Joshua D. Campbell, Jiehui Deng, Patrick H. Lizotte, Heather Silver, Roderick T. Bronson, Jie Bin Liu, Yuanwang Pan, Val Pyon, Catríona M. Dowling, Eleni Papadopoulos, Ting Chen, Zhong Wu, Jin Zhou, Hua Zhang, and Josephine Hai
- Abstract
CRISPR/Cas9 guides, primers and sequencing results
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- 2023
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11. Table S3 from Generation of Genetically Engineered Mouse Lung Organoid Models for Squamous Cell Lung Cancers Allows for the Study of Combinatorial Immunotherapy
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Kwok-Kin Wong, Adam J. Bass, Cassandra Thakurdin, Ming-Sound Tsao, Christine Ng, Lynette M. Sholl, Joshua D. Campbell, Jiehui Deng, Patrick H. Lizotte, Heather Silver, Roderick T. Bronson, Jie Bin Liu, Yuanwang Pan, Val Pyon, Catríona M. Dowling, Eleni Papadopoulos, Ting Chen, Zhong Wu, Jin Zhou, Hua Zhang, and Josephine Hai
- Abstract
Antibodies used for Immunohistochemistry, Immunofluroesence and immunblotting
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- 2023
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12. Table S5 from Generation of Genetically Engineered Mouse Lung Organoid Models for Squamous Cell Lung Cancers Allows for the Study of Combinatorial Immunotherapy
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Kwok-Kin Wong, Adam J. Bass, Cassandra Thakurdin, Ming-Sound Tsao, Christine Ng, Lynette M. Sholl, Joshua D. Campbell, Jiehui Deng, Patrick H. Lizotte, Heather Silver, Roderick T. Bronson, Jie Bin Liu, Yuanwang Pan, Val Pyon, Catríona M. Dowling, Eleni Papadopoulos, Ting Chen, Zhong Wu, Jin Zhou, Hua Zhang, and Josephine Hai
- Abstract
Pathway enrichment of differentially expressed genes (DEG) between mouse LSCC and LADC.
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- 2023
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13. Table S1 from Generation of Genetically Engineered Mouse Lung Organoid Models for Squamous Cell Lung Cancers Allows for the Study of Combinatorial Immunotherapy
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Kwok-Kin Wong, Adam J. Bass, Cassandra Thakurdin, Ming-Sound Tsao, Christine Ng, Lynette M. Sholl, Joshua D. Campbell, Jiehui Deng, Patrick H. Lizotte, Heather Silver, Roderick T. Bronson, Jie Bin Liu, Yuanwang Pan, Val Pyon, Catríona M. Dowling, Eleni Papadopoulos, Ting Chen, Zhong Wu, Jin Zhou, Hua Zhang, and Josephine Hai
- Abstract
Cell lines models
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- 2023
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14. Supplementary Figures S1-9 from Generation of Genetically Engineered Mouse Lung Organoid Models for Squamous Cell Lung Cancers Allows for the Study of Combinatorial Immunotherapy
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Kwok-Kin Wong, Adam J. Bass, Cassandra Thakurdin, Ming-Sound Tsao, Christine Ng, Lynette M. Sholl, Joshua D. Campbell, Jiehui Deng, Patrick H. Lizotte, Heather Silver, Roderick T. Bronson, Jie Bin Liu, Yuanwang Pan, Val Pyon, Catríona M. Dowling, Eleni Papadopoulos, Ting Chen, Zhong Wu, Jin Zhou, Hua Zhang, and Josephine Hai
- Abstract
Figures S1-9
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- 2023
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15. Histone Deacetylase 6 Inhibition Exploits Selective Metabolic Vulnerabilities in LKB1 Mutant, KRAS Driven NSCLC
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Hua Zhang, Christopher S. Nabel, Dezhi Li, Ruth Í. O’Connor, Caroline R. Crosby, Sarah M. Chang, Yuan Hao, Robyn Stanley, Soumyadip Sahu, Daniel S. Levin, Ting Chen, Sittinon Tang, Hsin-Yi Huang, Mary Meynardie, Janaye Stephens, Fiona Sherman, Alison Chafitz, Naoise Costelloe, Daniel A. Rodrigues, Hilda Fogarty, Miranda G. Kiernan, Fiona Cronin, Eleni Papadopoulos, Magdalena Ploszaj, Vajira Weerasekara, Jiehui Deng, Patrick Kiely, Nabeel Bardeesy, Matthew G. Vander Heiden, Triona Ni Chonghaile, Catríona M. Dowling, and Kwok-Kin Wong
- Subjects
Pulmonary and Respiratory Medicine ,Oncology - Published
- 2023
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16. Continuous Liquid-Phase Upgrading of Dihydroxyacetone to Lactic Acid over Metal Phosphate Catalysts
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Giada Innocenti, Carsten Sievers, Giuseppe Fornasari, Andrew J. Medford, Fabrizio Cavani, Eleni Papadopoulos, and Giada Innocenti, Eleni Papadopoulos, Giuseppe Fornasari, Fabrizio Cavani, Andrew J. Medford, Carsten Sievers
- Subjects
Order of reaction ,010405 organic chemistry ,Inorganic chemistry ,Aqueous two-phase system ,food and beverages ,Dihydroxyacetone ,General Chemistry ,mass-transfer, kinetic, second-order reaction, plug flow reactor, deactivation, pyruvaldehyde, acid catalysts ,010402 general chemistry ,Phosphate ,01 natural sciences ,Catalysis ,0104 chemical sciences ,Lactic acid ,chemistry.chemical_compound ,chemistry ,Pyruvaldehyde ,Plug flow reactor model - Abstract
The performance of Brønsted- and Lewis-acidic La, Nb, and Zr phosphates (LaPO, NbPO, and ZrPO) during the aqueous phase conversion of dihydroxyacetone (DHA) to lactic acid (LA) is investigated using a fixed-bed reactor. Mass-transfer phenomena are thoroughly investigated, and the masstransfer coefficient is deconvoluted from the intrinsic kinetic constant for each catalyst to enable the quantitative assessment of both. NbPO is found to be masstransfer-limited. Despite this limitation, NbPO shows the highest yield of LA at 36%. The reaction over ZrPO is not transport-limited, allowing for a rigorous analysis of intrinsic kinetics. This analysis shows that the conversion of DHA into pyruvaldehyde (PVA) follows a second-order reaction mechanism via a dimeric intermediate, which consolidates previous reports in the literature. Additionally, a correlation between LA production and the carbon missing from the carbon balance (carbon loss) is observed. Finally, NbPO and ZrPO show stable performance up to 10 h on stream at 150 °C. After 15 h of reaction, the PVA yield increases at the expense of LA with NbPO. This is ascribed to the deactivation of the active sites necessary to produce LA, which are different from the sites that produce PVA.This hypothesis is supported by the characterization of the spent catalyst with 13C magic-angle spinning nuclear magnetic resonance and attenuated total reflectance infrared spectroscopy.
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- 2020
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17. Targeting HER2 Exon 20 Insertion–Mutant Lung Adenocarcinoma with a Novel Tyrosine Kinase Inhibitor Mobocertinib
- Author
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Hua Zhang, Haiquan Chen, Sittinon Tang, Shougen Cao, Yuanwang Pan, Victor M. Rivera, Shuai Li, Fei Li, Kwan Ho Tang, Hai Hu, Chengwei Peng, Francois Gonzalvez, Hailin Ding, Jiehui Deng, Johara Chouitar, Han Han, Sylvie Vincent, Theresa E. Baker, Michael Fitzgerald, Val Pyon, Ting Chen, Zhendong Gao, Rachael L. Brake, Eleni Papadopoulos, David H. Peng, Jiansheng Wu, Cassandra Thakurdin, Kwok-Kin Wong, and Shengwu Liu
- Subjects
Cancer Research ,medicine.drug_class ,Afatinib ,T cell ,Poziotinib ,Biology ,medicine.disease ,Tyrosine-kinase inhibitor ,Exon ,medicine.anatomical_structure ,Oncology ,Neratinib ,medicine ,Cancer research ,Adenocarcinoma ,skin and connective tissue diseases ,Lung cancer ,medicine.drug - Abstract
No targeted treatments are currently approved for HER2 exon 20 insertion–mutant lung adenocarcinoma patients. Mobocertinib (TAK-788) is a potent irreversible tyrosine kinase inhibitor (TKI) designed to target human epidermal growth factor receptor 2 (HER2/ERBB2) exon 20 insertion mutations. However, the function of mobocertinib on HER2 exon 20 insertion–mutant lung cancer is still unclear. Here we conducted systematic characterization of preclinical models to understand the activity profile of mobocertinib against HER2 exon 20 insertions. In HER2 exon 20 insertion–mutant cell lines, the IC50 of mobocertinib was higher than poziotinib and comparable with or slightly lower than afatinib, neratinib, and pyrotinib. Mobocertinib had the lowest HER2 exon 20 insertion IC50/wild-type (WT) EGFR IC50 ratio, indicating that mobocertinib displayed the best selectivity profile in these models. Also, mobocertinib showed strong inhibitory activity in HER2 exon 20YVMA allograft and patient-derived xenograft models. In genetically engineered mouse models, HER2 exon 20G776>VC lung tumors exhibited a sustained complete response to mobocertinib, whereas HER2 exon 20YVMA tumors showed only partial and transient response. Combined treatment with a second antibody–drug conjugate (ADC) against HER2, ado-trastuzumab emtansine (T-DM1), synergized with mobocertinib in HER2 exon 20YVMA tumors. In addition to the tumor cell autonomous effect, sustained tumor growth control derived from M1 macrophage infiltration and CD4+ T-cell activation. These findings support the ongoing clinical development of mobocertinib (NCT02716116) and provide a rationale for future clinical evaluation of T-DM1 combinational therapy in HER2 exon 20YVMA insertion–mutant lung adenocarcinoma patients. Significance: This study elucidates the potent inhibitory activity of mobocertinib against HER2 exon 20 insertion–mutant lung cancer and the synergic effect of combined mobocertinib and T-DM1, providing a strong rationale for clinical investigation.
- Published
- 2021
- Full Text
- View/download PDF
18. ULK1 inhibition overcomes compromised antigen presentation and restores antitumor immunity in LKB1 mutant lung cancer
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Aristotelis Tsirigos, Subhadip Mukhopadhyay, Ting Chen, Mark R. Philips, Jiehui Deng, Hailin Ding, Val Pyon, Ian M. Ahearn, Fei Li, Mirna Bulatović, Antonio Marzio, Justin F. Gainor, Shuai Li, Cassandra Thakurdin, Heather Silver, Peter S. Hammerman, David H. Peng, Eli Rothenberg, John V. Heymach, Michele Pagano, Vajira K. Weerasekara, Yuanwang Pan, Hai Hu, Nathanael S. Gray, Charles M. Perou, Aatish Thennavan, Thales Papagiannakopoulos, Han Han, Baishan Jiang, John T. Poirier, Eleni Papadopoulos, Igor Dolgalev, Kwok-Kin Wong, Gordon J. Freeman, Charles M. Rudin, Nabeel Bardeesy, Eric S. Wang, and Jie Li
- Subjects
Cancer Research ,Antigen Presentation ,Lung Neoplasms ,biology ,Antigen processing ,business.industry ,medicine.medical_treatment ,Antigen presentation ,Autophagy ,Intracellular Signaling Peptides and Proteins ,Cancer ,Immunotherapy ,medicine.disease ,Article ,Immune system ,Oncology ,Carcinoma, Non-Small-Cell Lung ,medicine ,biology.protein ,Cancer research ,Autophagy-Related Protein-1 Homolog ,Humans ,Antibody ,Lung cancer ,business - Abstract
Inactivating mutations in LKB1/STK11 are present in roughly 20% of nonsmall cell lung cancers (NSCLC) and portend poor response to anti-PD-1 immunotherapy. Unexpectedly, we found that LKB1 deficiency correlated with elevated tumor mutational burden (TMB) in NSCLCs from nonsmokers and genetically engineered mouse models, despite the frequent association between high-TMB and anti-PD-1 treatment efficacy. However, LKB1 deficiency also suppressed antigen processing and presentation, which are associated with compromised immunoproteasome activity and increased autophagic flux. Immunoproteasome activity and antigen presentation were restored by inhibiting autophagy through targeting the ATG1/ULK1 pathway. Accordingly, ULK1 inhibition synergized with PD-1 antibody blockade, provoking effector T-cell expansion and tumor regression in Lkb1-mutant tumor models. This study reveals an interplay between the immunoproteasome and autophagic catabolism in antigen processing and immune recognition, and proposes the therapeutic potential of dual ULK1 and PD-1 inhibition in LKB1-mutant NSCLC as a strategy to enhance antigen presentation and to promote antitumor immunity. Wong and colleagues show that LKB1-deficient lung tumors are sensitive to autophagy inhibition, which can restore impaired antigen presentation and antitumor immune responses, and propose dual targeting of ULK1 and PD-1 for these tumors.
- Published
- 2021
19. Targeting
- Author
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Han, Han, Shuai, Li, Ting, Chen, Michael, Fitzgerald, Shengwu, Liu, Chengwei, Peng, Kwan Ho, Tang, Shougen, Cao, Johara, Chouitar, Jiansheng, Wu, David, Peng, Jiehui, Deng, Zhendong, Gao, Theresa E, Baker, Fei, Li, Hua, Zhang, Yuanwang, Pan, Hailin, Ding, Hai, Hu, Val, Pyon, Cassandra, Thakurdin, Eleni, Papadopoulos, Sittinon, Tang, Francois, Gonzalvez, Haiquan, Chen, Victor M, Rivera, Rachael, Brake, Sylvie, Vincent, and Kwok-Kin, Wong
- Subjects
Lung Neoplasms ,Receptor, ErbB-2 ,Adenocarcinoma of Lung ,Apoptosis ,Exons ,Mice, SCID ,Ado-Trastuzumab Emtansine ,Xenograft Model Antitumor Assays ,Article ,Gene Expression Regulation, Neoplastic ,Mice ,INDEL Mutation ,Mice, Inbred NOD ,Antibodies, Bispecific ,Antineoplastic Combined Chemotherapy Protocols ,Tumor Cells, Cultured ,Animals ,Humans ,Female ,skin and connective tissue diseases ,Cell Proliferation - Abstract
No targeted treatments are currently approved for HER2 exon 20 insertion-mutant lung adenocarcinoma patients. Mobocertinib (TAK-788) is a potent irreversible tyrosine kinase inhibitor (TKI) designed to target human epidermal growth factor receptor 2 (HER2/ERBB2) exon 20 insertion mutations. However, the function of mobocertinib on HER2 exon 20 insertion-mutant lung cancer is still unclear. Here we conducted systematic characterization of pre-clinical models to understand the activity profile of mobocertinib against HER2 exon 20 insertions. In HER2 exon 20 insertion mutant cell lines, the IC(50) of mobocertinib was higher than poziotinib and comparable or slightly lower than afatinib, neratinib, and pyrotinib. Mobocertinib had the lowest HER2 exon 20 insertion IC(50) / WT EGFR IC(50) ratio, indicating that mobocertinib displayed the best selectivity profile in these models. Also, mobocertinib showed strong inhibitory activity in HER2 exon 20(YVMA) allograft and patient-derived xenograft models. In genetically engineered mouse models, HER2 exon 20(G776>VC) lung tumors exhibited a sustained complete response to mobocertinib, while HER2 exon 20(YVMA) tumors showed only partial and transient response. Combined treatment with a second antibody-drug conjugate (ADC) against HER2, ado-trastuzumab emtansine (T-DM1) synergized with mobocertinib in HER2 exon 20(YVMA) tumors. In addition to the tumor cell autonomous effect, sustained tumor growth control derived from M1 macrophage infiltration and CD4(+) T cell activation. These findings support the ongoing clinical development of mobocertinib (NCT02716116) and provide a rationale for future clinical evaluation of T-DM1 combinational therapy in HER2 exon 20(YVMA) insertion-mutant lung adenocarcinoma patients.
- Published
- 2021
20. Multiple screening approaches reveal HDAC6 as a novel regulator of glycolytic metabolism in triple-negative breast cancer
- Author
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Alec C. Kimmelman, Jochen H. M. Prehn, Brian Mooney, Triona Ni Chonghaile, Michael T. Hemann, Hua Zhang, Heiko Düssmann, Eugene T. Dillon, Darran P. O'Connor, Andreas U. Lindner, Catríona M. Dowling, Justin R. Pritchard, Gerard Cagney, Anthony Letai, Kwok-Kin Wong, James E. Bradner, Rachel Bleach, Kieran Wynne, Kathryn Haley, Alessandra Di Grande, Kate E.R. Hollinshead, Jennifer L. Guerriero, Anita K. Mehta, and Eleni Papadopoulos
- Subjects
Regulator ,Apoptosis ,Triple Negative Breast Neoplasms ,Biology ,Histone Deacetylase 6 ,03 medical and health sciences ,0302 clinical medicine ,Breast cancer ,Cell Line, Tumor ,medicine ,Humans ,Early Detection of Cancer ,Research Articles ,Triple-negative breast cancer ,Cell Proliferation ,Cancer ,030304 developmental biology ,0303 health sciences ,Multidisciplinary ,SciAdv r-articles ,Cell Biology ,HDAC6 ,medicine.disease ,In vitro ,3. Good health ,Histone Deacetylase Inhibitors ,Mechanism of action ,030220 oncology & carcinogenesis ,Cancer research ,Histone deacetylase ,medicine.symptom ,Research Article - Abstract
Discovery of a new HDAC6 inhibitor reveals role for HDAC6 in the regulation of glycolytic metabolism., Triple-negative breast cancer (TNBC) is a subtype of breast cancer without a targeted form of therapy. Unfortunately, up to 70% of patients with TNBC develop resistance to treatment. A known contributor to chemoresistance is dysfunctional mitochondrial apoptosis signaling. We set up a phenotypic small-molecule screen to reveal vulnerabilities in TNBC cells that were independent of mitochondrial apoptosis. Using a functional genetic approach, we identified that a “hit” compound, BAS-2, had a potentially similar mechanism of action to histone deacetylase inhibitors (HDAC). An in vitro HDAC inhibitor assay confirmed that the compound selectively inhibited HDAC6. Using state-of-the-art acetylome mass spectrometry, we identified glycolytic substrates of HDAC6 in TNBC cells. We confirmed that inhibition or knockout of HDAC6 reduced glycolytic metabolism both in vitro and in vivo. Through a series of unbiased screening approaches, we have identified a previously unidentified role for HDAC6 in regulating glycolytic metabolism.
- Published
- 2021
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21. P52.04 Histone Deacetylase 6 Inhibition Reveals Metabolic Vulnerabilities in KRAS Non-Small Cell Lung Cancer
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Emily A. Vucic, Catríona M. Dowling, Kwok K. Wong, N. Costelloe, Eleni Papadopoulos, Hua Zhang, and C. Nabel
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Pulmonary and Respiratory Medicine ,Oncology ,business.industry ,medicine ,Cancer research ,KRAS ,Non small cell ,HDAC6 ,Lung cancer ,medicine.disease ,business ,medicine.disease_cause - Published
- 2021
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22. MA11.02 Targeting HER2 Exon 20–Mutant Lung Adenocarcinoma with a Novel Tyrosine Kinase Inhibitor, Mobocertinib
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Hao Chen, Zhendong Gao, Hailin Ding, Jiansheng Wu, Yuanwang Pan, Michael Fitzgerald, Sittinon Tang, Kwan Ho Tang, Cassandra Thakurdin, Sylvie Vincent, Rachael L. Brake, Kwok K. Wong, Ting Chen, S. Cao, Val Pyon, C. Peng, Jiehui Deng, Victor M. Rivera, Theresa E. Baker, Fei Li, Hai Hu, Francois Gonzalvez, David H. Peng, Simin Liu, Shihua Li, Eleni Papadopoulos, Johara Chouitar, Han Han, and Hua Zhang
- Subjects
Pulmonary and Respiratory Medicine ,Lung ,business.industry ,medicine.drug_class ,Mutant ,medicine.disease ,Tyrosine-kinase inhibitor ,Exon ,medicine.anatomical_structure ,Oncology ,medicine ,Cancer research ,Adenocarcinoma ,business - Published
- 2021
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23. Generation of Genetically Engineered Mouse Lung Organoid Models for Squamous Cell Lung Cancers Allows for the Study of Combinatorial Immunotherapy
- Author
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Lynette M. Sholl, Ting Chen, Josephine Hai, Zhong Wu, Patrick H. Lizotte, Cassandra Thakurdin, Jiehui Deng, Christine Ng, Yuanwang Pan, Joshua D. Campbell, Adam J. Bass, Catríona M. Dowling, Jin Zhou, Val Pyon, Roderick T. Bronson, Eleni Papadopoulos, Heather Silver, Jie Bin Liu, Kwok-Kin Wong, Ming-Sound Tsao, and Hua Zhang
- Subjects
0301 basic medicine ,Cancer Research ,Lung Neoplasms ,medicine.medical_treatment ,Antigen presentation ,Cell ,Gene Expression ,Mice, Transgenic ,Biology ,Article ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Lymphocytes, Tumor-Infiltrating ,SOX2 ,Genome editing ,Cell Line, Tumor ,medicine ,Biomarkers, Tumor ,Cytotoxic T cell ,Animals ,Humans ,Lung ,Gene Editing ,Immunotherapy ,Combined Modality Therapy ,Immunohistochemistry ,Xenograft Model Antitumor Assays ,Immune checkpoint ,Organoids ,Disease Models, Animal ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,Genetically Engineered Mouse ,Cancer research ,Carcinoma, Squamous Cell ,Genetic Engineering ,Biomarkers - Abstract
Purpose: Lung squamous cell carcinoma (LSCC) is a deadly disease for which only a subset of patients responds to immune checkpoint blockade (ICB) therapy. Therefore, preclinical mouse models that recapitulate the complex genetic profile found in patients are urgently needed. Experimental Design: We used CRISPR genome editing to delete multiple tumor suppressors in lung organoids derived from Cre-dependent SOX2 knock-in mice. We investigated both the therapeutic efficacy and immunologic effects accompanying combination PD-1 blockade and WEE1 inhibition in both mouse models and LSCC patient-derived cell lines. Results: We show that multiplex gene editing of mouse lung organoids using the CRISPR–Cas9 system allows for efficient and rapid means to generate LSCCs that closely mimic the human disease at the genomic and phenotypic level. Using this genetically defined mouse model and three-dimensional tumoroid culture system, we show that WEE1 inhibition induces DNA damage that primes the endogenous type I IFN and antigen presentation system in primary LSCC tumor cells. These events promote cytotoxic T-cell–mediated clearance of tumor cells and reduce the accumulation of tumor-infiltrating neutrophils. Beneficial immunologic features of WEE1 inhibition are further enhanced by the addition of anti–PD-1 therapy. Conclusions: We developed a mouse model system to investigate a novel combinatory approach that illuminates a clinical path hypothesis for combining ICB with DNA damage–inducing therapies in the treatment of LSCC.
- Published
- 2019
24. CDK7 Inhibition Potentiates Genome Instability Triggering Anti-tumor Immunity in Small Cell Lung Cancer
- Author
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Max M. Quinn, Alan L. Leggett, Jack Donaghue, Tinghu Zhang, Annan Yang, Xuzhu Zhang, Ruben Dries, Eric S. Wang, Catríona M. Dowling, Belen Sundberg, William G. Kaelin, Nicholas Kwiatkowski, Richard Bonneau, Matthew G. Oser, Fei Li, Zhixiang He, Vladislav O. Sviderskiy, Kwok-Kin Wong, Gordon J. Freeman, Kandarp Jani, Guo-Cheng Yuan, Kate D. Sutherland, Dayanne M. Castro, Eleni Papadopoulos, Nathanael S. Gray, Heather Silver, Andrew J. Aguirre, Brian Diskin, Mirna Bulatović, Cassandra Thakurdin, Michela Ranieri, Jiehui Deng, Eli Rothenberg, Alexandra R. Rabin, Ting Chen, Ariena Kersbergen, Yandong Yin, Qingyuan Huang, George Miller, Vamsidhar Velcheti, Camilla L. Christensen, Christina Almonte, Val Pyon, Yuanwang Pan, Kristen E. Labbe, Shuai Li, Hua Zhang, Peter S. Hammerman, and Han Han
- Subjects
CD4-Positive T-Lymphocytes ,Male ,0301 basic medicine ,Genome instability ,Cancer Research ,Lung Neoplasms ,medicine.medical_treatment ,T cell ,Programmed Cell Death 1 Receptor ,Antineoplastic Agents ,CD8-Positive T-Lymphocytes ,Chemokine CXCL9 ,Genomic Instability ,Interferon-gamma ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Cyclin-dependent kinase ,PD-L1 ,medicine ,Animals ,Humans ,Pyrroles ,Inflammation ,Micronucleus Tests ,biology ,Tumor Necrosis Factor-alpha ,Immunotherapy ,Cell cycle ,Small Cell Lung Carcinoma ,Cyclin-Dependent Kinases ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,Immune System ,030220 oncology & carcinogenesis ,Cancer research ,biology.protein ,Pyrazoles ,Female ,Cyclin-Dependent Kinase-Activating Kinase ,DNA Damage ,Signal Transduction - Abstract
Cyclin-dependent kinase 7 (CDK7) is a central regulator of the cell cycle and gene transcription. However, little is known about its impact on genomic instability and cancer immunity. Using a selective CDK7 inhibitor, YKL-5-124, we demonstrated that CDK7 inhibition predominately disrupts cell-cycle progression and induces DNA replication stress and genome instability in small cell lung cancer (SCLC) while simultaneously triggering immune-response signaling. These tumor-intrinsic events provoke a robust immune surveillance program elicited by T cells, which is further enhanced by the addition of immune-checkpoint blockade. Combining YKL-5-124 with anti-PD-1 offers significant survival benefit in multiple highly aggressive murine models of SCLC, providing a rationale for new combination regimens consisting of CDK7 inhibitors and immunotherapies.
- Published
- 2020
- Full Text
- View/download PDF
25. A thermal and rheological investigation during the complex cure of a two-component thermoset polyurethane
- Author
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Eleni Papadopoulos, Stephen Clarke, Milena Ginic-Markovic, Papadopoulos, E, Ginic-Markovic, Milena, and Clarke, Stephen Ross
- Subjects
chemistry.chemical_classification ,Activation energy ,DSC ,Gelation ,Isoconversional analysis ,Polyurethanes ,Viscosity buildup ,Materials science ,Polymers and Plastics ,technology, industry, and agriculture ,Thermosetting polymer ,Thermodynamics ,General Chemistry ,Polymer ,Isothermal process ,Surfaces, Coatings and Films ,chemistry.chemical_compound ,Differential scanning calorimetry ,chemistry ,Polymer chemistry ,Materials Chemistry ,Glass transition ,Curing (chemistry) ,Polyurethane - Abstract
The complex cure kinetics of the reaction between oligomeric diphenylmethane diisocyanate (PMDI) and glycerol was characterized through thermal and rheological techniques. Isoconversional analysis of Differential scanning calorimetry (DSC) data resulted in the activation energy varying with conversion. Isothermal analysis gave activation energies ranging from 5 kJ/mol to 33.7 kJ/ mol, whereas nonisothermal data gave values for the activation energy ranging from 49.5 to 55 kJ/mol. Incomplete cure was evident in isothermal DSC, becoming diffusion controlled in the final stages of cure. DMA analysis on the cured material gave a glass transition temperature of 104 ± 3°C, which was evidence for vitrification of the curing system. The primary and secondary hydroxyl group reactivity was dependant on the isothermal cure temperature. Rheological studies of viscosity increase and tan δ changes with time revealed a complex cure process, with primary and secondary hydroxyl reactivity also showing dependence on isothermal cure temperatures, reflecting similar results obtained from isothermal DSC studies. The independence of tan δ on frequency was used to determine the point where the polymer formed an infinite network and was no longer able to flow, providing an overall activation energy attained at the gel point of 77.4 ± 4.4 kJ/mol. © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2009
- Published
- 2009
- Full Text
- View/download PDF
26. Reaction kinetics of polyurethane formation using a commercial oligomeric diisocyanate resin studied by calorimetric and rheological methods
- Author
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Eleni Papadopoulos, Milena Ginic-Markovic, Stephen Clarke, Papadopoulos, E, Ginic-Markovic, Milena, and Clarke, Stephen Ross
- Subjects
Polymers and Plastics ,Chemistry ,Organic Chemistry ,Kinetics ,Activation energy ,Condensed Matter Physics ,Isocyanate ,activation energy ,DSC ,gelation ,polyurethanes ,viscosity build up ,Chemical kinetics ,Reaction rate ,chemistry.chemical_compound ,Differential scanning calorimetry ,Castor oil ,Polymer chemistry ,Materials Chemistry ,medicine ,Physical and Theoretical Chemistry ,medicine.drug ,Polyurethane - Abstract
Reaction rate and kinetics of cure between PMDI and castor oil, a tri-functional polyol, for stoichiometric and off-stoichiometric mole ratios, were studied through isoconversional analysis of DSC data and through gelation times and viscosity build up obtained through rheological techniques. The cure kinetics of the polyurethane reaction as monitored using different techniques gave similar activation energies for the stoichiometric ratio. Isoconversional analysis of DSC data showed a competitive reaction scheme for the stoichiometric system, suggesting the presence of isocyanate groups with different reactivities in the PMDI, which was further substantiated in rheological investigations.
- Published
- 2008
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