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1. High CTLA-4 gene expression is an independent good prognosis factor in breast cancer patients, especially in the HER2-enriched subtype

Author

Yoel G. Montoyo-Pujol, José J. Ponce, Silvia Delgado-García, Tina A. Martín, Hortensia Ballester, Elena Castellón-Molla, Angela Ramos-Montoya, Inmaculada Lozano-Cubo, J. Miguel Sempere-Ortells, and Gloria Peiró

Subjects
Breast carcinoma, Immune checkpoints, mRNA expression, CTLA-4, HER2-enriched, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282, Cytology, QH573-671
Abstract

Abstract Background Breast cancer (BC) is the most common cancer in women and the leading cause of cancer-related death worldwide. This heterogeneous disease has been historically considered a non-immunogenic type of cancer. However, recent advances in immunotherapy have increased the interest in knowing the role of the immune checkpoints (IC) and other immune regulation pathways in this neoplasia. Methods In this retrospective study, we evaluated the correlation of mRNA expression of CTLA-4, PDCD1 (PD1), CD274 (PD-L1), PDCD1LG2 (PD-L2), CD276 (B7-H3), JAK2, and FOXO1 with clinicopathological factors and BC patient’s outcome by real-time quantitative polymerase chain reaction (qPCR). Results Our results showed that immunoregulatory gene expression depends on BC immunophenotype being CTLA-4 and PDCD1 (PD1) overexpressed on triple-negative/basal-like (TN/BL) and luminal B/HER2-positive phenotypes, respectively, and CD276 (B7-H3), JAK2 and FOXO1 associated with both luminal A and luminal B/HER2-negative tumors. In addition, we found that these genes can also be related to aggressive and non-aggressive clinicopathological characteristics in BC. Finally, survival analysis showed that CTLA-4 expression levels emerge as a significant independent factor of good prognosis in BC patients, especially in the HER2-enriched subtype. Conclusion Considering all these data, we can conclude that the expression of immunoregulatory genes depends on tumor phenotype and has potential clinical implications in BC patients.

Published
2024
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3. VEGF pathway inhibition potentiates PARP inhibitor efficacy in ovarian cancer independent of BRCA status

Author

Francesca Bizzaro, Ilaria Fuso Nerini, Molly A. Taylor, Alessia Anastasia, Massimo Russo, Giovanna Damia, Federica Guffanti, Francesca Guana, Paola Ostano, Lucia Minoli, Maureen M. Hattersley, Stephanie Arnold, Antonio Ramos-Montoya, Stuart C. Williamson, Alessandro Galbiati, Jelena Urosevic, Elisabetta Leo, Ugo Cavallaro, Carmen Ghilardi, Simon T. Barry, Maria Rosa Bani, and Raffaella Giavazzi

Subjects
Ovarian cancer, Patient-derived xenograft, PARP inhibitor, VEGF pathway inhibitor, BRCA, Olaparib, Diseases of the blood and blood-forming organs, RC633-647.5, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Poly ADP-ribose polymerase inhibitors (PARPi) have transformed ovarian cancer (OC) treatment, primarily for tumours deficient in homologous recombination repair. Combining VEGF-signalling inhibitors with PARPi has enhanced clinical benefit in OC. To study drivers of efficacy when combining PARP inhibition and VEGF-signalling, a cohort of patient-derived ovarian cancer xenografts (OC-PDXs), representative of the molecular characteristics and drug sensitivity of patient tumours, were treated with the PARPi olaparib and the VEGFR inhibitor cediranib at clinically relevant doses. The combination showed broad anti-tumour activity, reducing growth of all OC-PDXs, regardless of the homologous recombination repair (HRR) mutational status, with greater additive combination benefit in tumours poorly sensitive to platinum and olaparib. In orthotopic models, the combined treatment reduced tumour dissemination in the peritoneal cavity and prolonged survival. Enhanced combination benefit was independent of tumour cell expression of receptor tyrosine kinases targeted by cediranib, and not associated with change in expression of genes associated with DNA repair machinery. However, the combination of cediranib with olaparib was effective in reducing tumour vasculature in all the OC-PDXs. Collectively our data suggest that olaparib and cediranib act through complementary mechanisms affecting tumour cells and tumour microenvironment, respectively. This detailed analysis of the combined effect of VEGF-signalling and PARP inhibitors in OC-PDXs suggest that despite broad activity, there is no dominant common mechanistic inter-dependency driving therapeutic benefit.

Published
2021
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5. A microfluidic system that replicates pharmacokinetic (PK) profiles in vitro improves prediction of in vivo efficacy in preclinical models.

Author

Dharaminder Singh, Sudhir P Deosarkar, Elaine Cadogan, Vikki Flemington, Alysha Bray, Jingwen Zhang, Ronald S Reiserer, David K Schaffer, Gregory B Gerken, Clayton M Britt, Erik M Werner, Francis D Gibbons, Tomasz Kostrzewski, Christopher E Chambers, Emma J Davies, Antonio Ramos Montoya, Jacqueline H L Fok, David Hughes, Kristin Fabre, Matthew P Wagoner, John P Wikswo, and Clay W Scott

Subjects
Biology (General), QH301-705.5
Abstract

Test compounds used on in vitro model systems are conventionally delivered to cell culture wells as fixed concentration bolus doses; however, this poorly replicates the pharmacokinetic (PK) concentration changes seen in vivo and reduces the predictive value of the data. Herein, proof-of-concept experiments were performed using a novel microfluidic device, the Microformulator, which allows in vivo like PK profiles to be applied to cells cultured in microtiter plates and facilitates the investigation of the impact of PK on biological responses. We demonstrate the utility of the device in its ability to reproduce in vivo PK profiles of different oncology compounds over multiweek experiments, both as monotherapy and drug combinations, comparing the effects on tumour cell efficacy in vitro with efficacy seen in in vivo xenograft models. In the first example, an ERK1/2 inhibitor was tested using fixed bolus dosing and Microformulator-replicated PK profiles, in 2 cell lines with different in vivo sensitivities. The Microformulator-replicated PK profiles were able to discriminate between cell line sensitivities, unlike the conventional fixed bolus dosing. In a second study, murine in vivo PK profiles of multiple Poly(ADP-Ribose) Polymerase 1/2 (PARP) and DNA-dependent protein kinase (DNA-PK) inhibitor combinations were replicated in a FaDu cell line resulting in a reduction in cell growth in vitro with similar rank ordering to the in vivo xenograft model. Additional PK/efficacy insight into theoretical changes to drug exposure profiles was gained by using the Microformulator to expose FaDu cells to the DNA-PK inhibitor for different target coverage levels and periods of time. We demonstrate that the Microformulator enables incorporating PK exposures into cellular assays to improve in vitro-in vivo translation understanding for early therapeutic insight.

Published
2022
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6. High CTLA-4 gene expression is an independent good prognosis factor in breast cancer patients, especially in the HER2-enriched subtype

Author

Montoyo-Pujol, Yoel Genaro, primary, Ponce, Jose, additional, Delgado-García, Silvia, additional, Martín, Tina A., additional, Ballester, Hortensia, additional, Castellón-Molla, Elena, additional, Ramos-Montoya, Angela, additional, Lozano-Cubo, Inmaculada, additional, Sempere-Ortells, José Miguel, additional, and Peiró, Gloria, additional

Published
2024
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7. Independence of HIF1a and androgen signaling pathways in prostate cancer

Author

Maxine G. B. Tran, Becky A. S. Bibby, Lingjian Yang, Franklin Lo, Anne Y. Warren, Deepa Shukla, Michelle Osborne, James Hadfield, Thomas Carroll, Rory Stark, Helen Scott, Antonio Ramos-Montoya, Charlie Massie, Patrick Maxwell, Catharine M. L. West, Ian G. Mills, and David E. Neal

Subjects
Prostate cancer, Androgen signaling, HIF1a signaling, Hypoxia, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background Therapeutic targeting of the androgen signaling pathway is a mainstay treatment for prostate cancer. Although initially effective, resistance to androgen targeted therapies develops followed by disease progression to castrate-resistant prostate cancer (CRPC). Hypoxia and HIF1a have been implicated in the development of resistance to androgen targeted therapies and progression to CRCP. The interplay between the androgen and hypoxia/HIF1a signaling axes was investigated. Methods In vitro stable expression of HIF1a was established in the LNCaP cell line by physiological induction or retroviral transduction. Tumor xenografts with stable expression of HIF1a were established in castrated and non-castrated mouse models. Gene expression analysis identified transcriptional changes in response to androgen treatment, hypoxia and HIF1a. The binding sites of the AR and HIF transcription factors were identified using ChIP-seq. Results Androgen and HIF1a signaling promoted proliferation in vitro and enhanced tumor growth in vivo. The stable expression of HIF1a in vivo restored tumor growth in the absence of endogenous androgens. Hypoxia reduced AR binding sites whereas HIF binding sites were increased with androgen treatment under hypoxia. Gene expression analysis identified seven genes that were upregulated both by AR and HIF1a, of which six were prognostic. Conclusions The oncogenic AR, hypoxia and HIF1a pathways support prostate cancer development through independent signaling pathways and transcriptomic profiles. AR and hypoxia/HIF1a signaling pathways independently promote prostate cancer progression and therapeutic targeting of both pathways simultaneously is warranted.

Published
2020
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8. VEGF pathway inhibition potentiates PARP inhibitor efficacy in ovarian cancer independent of BRCA status

Author

Bizzaro, Francesca, Fuso Nerini, Ilaria, Taylor, Molly A., Anastasia, Alessia, Russo, Massimo, Damia, Giovanna, Guffanti, Federica, Guana, Francesca, Ostano, Paola, Minoli, Lucia, Hattersley, Maureen M., Arnold, Stephanie, Ramos-Montoya, Antonio, Williamson, Stuart C., Galbiati, Alessandro, Urosevic, Jelena, Leo, Elisabetta, Cavallaro, Ugo, Ghilardi, Carmen, Barry, Simon T., Bani, Maria Rosa, and Giavazzi, Raffaella

Published
2021
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10. Descripción morfométrica Trichomycteridae (Siluriformes) de las cuencas hidrográficas de la cordillera Chongón-Colonche, provincia de Santa Elena, Ecuador

Author

Pedro Guillermo Ramos Montoya and Antonio Torres Noboa

Subjects
trichomycteridae, relaciones morfométricas, crecimiento alométrico, morfométria geométrica, Chemistry, QD1-999, Plant ecology, QK900-989, Geology, QE1-996.5, Biology (General), QH301-705.5
Abstract

La presencia de diferentes grupos de peces de agua dulce son el resultado de eventos de especiación en la costa ecuatoriana, esto debido a los factores geomorfológicos y variaciones climáticas. La familia Trichomycteridae es un representante de este proceso evolutivo, sin embargo, existen escasos estudios. Este trabajo describió e identifico a los representantes de dicha familia en dos comunas en la cordillera Chongón - Colonche. Las especies identificadas fueron; 30 individuos para Trichomycterus taenia para Dos Mangas y 34 individuos como Trichomycterus cf. taenia para Loma Alta, mediante regresiones lineales se determinó que las relaciones entre las variables analizadas evidenciaron una tendencia lineal con un coeficiente de correlación superior a R = 0.89. Los valores de las pendientes (b) demostraron un crecimiento alométrico negativo (b

Published
2021
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11. AZD7648 is a potent and selective DNA-PK inhibitor that enhances radiation, chemotherapy and olaparib activity

Author

Jacqueline H. L. Fok, Antonio Ramos-Montoya, Mercedes Vazquez-Chantada, Paul W. G. Wijnhoven, Valeria Follia, Neil James, Paul M. Farrington, Ankur Karmokar, Sophie E. Willis, Jonathan Cairns, Jenni Nikkilä, David Beattie, Gillian M. Lamont, M. Raymond V. Finlay, Joanne Wilson, Aaron Smith, Lenka Oplustil O’Connor, Stephanie Ling, Stephen E. Fawell, Mark J. O’Connor, Simon J. Hollingsworth, Emma Dean, Frederick W. Goldberg, Barry R. Davies, and Elaine B. Cadogan

Subjects
Science
Abstract

DNA-dependent protein kinase (DNA-PK) plays a major role in the DNA damage response upon double-strand break formation. Here, the authors show that the DNA-PK inhibitor AZD7648, enhances the activity of radiotherapy, chemotherapy and the PARP inhibitor olaparib in multiple mouse tumour models.

Published
2019
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12. Estrés postraumático y resiliencia en estudiantes del quinto año de secundaria de instituciones educativas de Lima Sur en tiempos de pandemia

Author

Eduardo Samuel Ninamango Malqui, Judith María Luisa Bedoya Suárez, and Silvana Raquel Ramos-Montoya

Subjects
General Medicine
Abstract

La presente investigación tuvo como objetivo determinar la relación entre estrés postraumático y resiliencia en estudiantes del quinto año de secundaria de instituciones educativas de Lima Sur, en tiempos de pandemia. Participaron 206 estudiantes de quinto año de secundaria de instituciones educativas estatales y privadas de Lima Sur, de ambos sexos, cuyas edades oscilaron entre 15 y 17 años de edad. Los instrumentos utilizados fueron la Escala de Gravedad de Síntomas del Trastorno de Estrés Postraumático (EGS-R) de Echeburúa et al. (2016) y la Escala de Resiliencia de Wagnild y Young (1993). Los resultados indicaron que el 46,12% de los participantes presentó sintomatología clínicamente significativa de estrés postraumático. No se hallaron correlaciones entre las puntuaciones totales ni entre las dimensiones de la intensidad de los síntomas de estrés postraumático, por un lado, y la resiliencia, por el otro. Se observaron diferencias significativas según sexo solo en los niveles de estrés postraumático (total y dimensiones) teniendo las mujeres un puntaje más alto; en cuanto a resiliencia se observó una puntuación significativamente mayor en el factor de ecuanimidad en las mujeres.

Published
2023

13. Identification of potential therapeutic targets in prostate cancer through a cross‐species approach

Author

Sarah Jurmeister, Antonio Ramos‐Montoya, Chiranjeevi Sandi, Nelma Pértega‐Gomes, Karan Wadhwa, Alastair D Lamb, Mark J Dunning, Jan Attig, Jason S Carroll, Lee GD Fryer, Sérgio L Felisbino, and David E Neal

Subjects
cross‐species analysis, MELK, mouse models, new cancer targets, prostate cancer, Medicine (General), R5-920, Genetics, QH426-470
Abstract

Abstract Genetically engineered mouse models of cancer can be used to filter genome‐wide expression datasets generated from human tumours and to identify gene expression alterations that are functionally important to cancer development and progression. In this study, we have generated RNAseq data from tumours arising in two established mouse models of prostate cancer, PB‐Cre/PtenloxP/loxP and p53loxP/loxPRbloxP/loxP, and integrated this with published human prostate cancer expression data to pinpoint cancer‐associated gene expression changes that are conserved between the two species. To identify potential therapeutic targets, we then filtered this information for genes that are either known or predicted to be druggable. Using this approach, we revealed a functional role for the kinase MELK as a driver and potential therapeutic target in prostate cancer. We found that MELK expression was required for cell survival, affected the expression of genes associated with prostate cancer progression and was associated with biochemical recurrence.

Published
2018
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15. Optimization of hERG and Pharmacokinetic Properties for Basic Dihydro-8

Author

Frederick W, Goldberg, Attilla K T, Ting, David, Beattie, Gillian M, Lamont, Charlene, Fallan, M Raymond V, Finlay, Beth, Williamson, Marianne, Schimpl, Alexander R, Harmer, Oladipupo B, Adeyemi, Pär, Nordell, Anna S, Cronin, Mercedes, Vazquez-Chantada, Derek, Barratt, Antonio, Ramos-Montoya, Elaine B, Cadogan, and Barry R, Davies

Abstract

The DNA-PK complex is activated by double-strand DNA breaks and regulates the non-homologous end-joining repair pathway; thus, targeting DNA-PK by inhibiting the DNA-PK catalytic subunit (DNA-PKcs) is potentially a useful therapeutic approach for oncology. A previously reported series of neutral DNA-PKcs inhibitors were modified to incorporate a basic group, with the rationale that increasing the volume of distribution while maintaining good metabolic stability should increase the half-life. However, adding a basic group introduced hERG activity, and basic compounds with modest hERG activity (IC

Published
2023

16. The DNA-PK Inhibitor AZD7648 Sensitizes Patient-Derived Ovarian Cancer Xenografts to Pegylated Liposomal Doxorubicin and Olaparib Preventing Abdominal Metastases

Author

Anastasia, A, Dellavedova, G, Ramos-Montoya, A, James, N, Chiorino, G, Russo, M, Baakza, H, Wilson, J, Ghilardi, C, Cadogan, E, Giavazzi, R, Rosa Bani, M, Alessia Anastasia, Giulia Dellavedova, Antonio Ramos-Montoya, Neil James, Giovanna Chiorino, Massimo Russo, Hana Baakza, Joanne Wilson, Carmen Ghilardi, Elaine B. Cadogan, Raffaella Giavazzi, Maria Rosa Bani, Anastasia, A, Dellavedova, G, Ramos-Montoya, A, James, N, Chiorino, G, Russo, M, Baakza, H, Wilson, J, Ghilardi, C, Cadogan, E, Giavazzi, R, Rosa Bani, M, Alessia Anastasia, Giulia Dellavedova, Antonio Ramos-Montoya, Neil James, Giovanna Chiorino, Massimo Russo, Hana Baakza, Joanne Wilson, Carmen Ghilardi, Elaine B. Cadogan, Raffaella Giavazzi, and Maria Rosa Bani

Abstract

Ovarian cancer is the deadliest gynecologic cancer, with a 5-year survival rate of 30%, when the disease has spread throughout the peritoneal cavity. We investigated the efficacy to delay disease progression by the DNA-dependent protein kinase (DNA-PK) inhibitor AZD7648, administered in combination with two of the therapeutic options for patient management: either pegylated liposomal doxorubicin (PLD) or the PARP inhibitor olaparib. Patient-derived ovarian cancer xenografts (OC-PDX) were transplanted subcutaneously to evaluate the effect of treatment on tumor growth, or orthotopically in the peritoneal cavity to evaluate the effect on metastatic spread. AZD7648 was administered orally in combination with PLD (dosed intravenously) or with olaparib (orally). To prove the inhibition of DNA-PK in the tumors, we measured pDNA-PKcs, pRPA32, and g H2AX, biomarkers of DNA-PK activity. AZD7648 enhanced the therapeutic efficacy of PLD in all the OC-PDXs tested, regardless of their BRCA status or sensitivity to cisplatin or PLD. The treatment caused disease stabilization, which persisted despite therapy discontinuation for tumors growing subcutaneously, and significantly impaired the abdominal metastatic dissemination, prolonging the lifespan of mice implanted orthotopically. AZD7648 potentiated the efficacy of olaparib in BRCA-deficient OC-PDXs but did not sensitize BRCA-proficient OC-PDXs to olaparib, despite an equivalent inhibition of DNA-PK, suggesting the need of a preexisting olaparib activity to benefit from the addition of AZD7648. This work suggests that AZD7648, an inhibitor of DNA-PK, dosed in combination with PLD or olaparib is an exciting therapeutic option that could benefit patients with ovarian cancer and should be explored in clinical trials.

Published
2022

17. pRAD50: a novel and clinically applicable pharmacodynamic biomarker of both ATM and ATR inhibition identified using mass spectrometry and immunohistochemistry

Author

Jones, Gemma N., Rooney, Claire, Griffin, Nicola, Roudier, Martine, Young, Lucy A., Garcia-Trinidad, Antonio, Hughes, Gareth D., Whiteaker, Jeffrey R., Wilson, Zena, Odedra, Rajesh, Zhao, Lei, Ivey, Richard G., Howat, William J., Harrington, Elizabeth A., Barrett, J. Carl, Ramos-Montoya, Antonio, Lau, Alan, Paulovich, Amanda G., Cadogan, Elaine B., and Pierce, Andrew J.

Published
2018
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18. Optimization of hERG and Pharmacokinetic Properties for Basic Dihydro-8H-purin-8-one Inhibitors of DNA-PK

Author

Frederick W. Goldberg, Attilla K. T. Ting, David Beattie, Gillian M. Lamont, Charlene Fallan, M. Raymond V. Finlay, Beth Williamson, Marianne Schimpl, Alexander R. Harmer, Oladipupo B. Adeyemi, Pär Nordell, Anna S. Cronin, Mercedes Vazquez-Chantada, Derek Barratt, Antonio Ramos-Montoya, Elaine B. Cadogan, and Barry R. Davies

Subjects
Organic Chemistry, Drug Discovery, Biochemistry
Published
2022

20. Supplementary Materials and Methods and Supplementary Tables 1-2 from Macrophage Activation Status Rather than Repolarization Is Associated with Enhanced Checkpoint Activity in Combination with PI3Kγ Inhibition

Author

Carnevalli, Larissa S., primary, Taylor, Molly A., primary, King, Matthew, primary, Coenen-Stass, Anna M.L., primary, Hughes, Adina M., primary, Bell, Sigourney, primary, Proia, Theresa A., primary, Wang, Yanjun, primary, Ramos-Montoya, Antonio, primary, Wali, Neha, primary, Carroll, Danielle, primary, Singh, Maneesh, primary, Moschetta, Michele, primary, Gutierrez, Pablo Morentin, primary, Gardelli, Cristina, primary, Critchlow, Susan E., primary, Klinowska, Teresa, primary, Fawell, Stephen E., primary, and Barry, Simon T., primary

Published
2023
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21. Supplementary Figure 1 from Salt-Inducible Kinase 2 Regulates Mitotic Progression and Transcription in Prostate Cancer

Author

Bon, Hélène, primary, Wadhwa, Karan, primary, Schreiner, Alexander, primary, Osborne, Michelle, primary, Carroll, Thomas, primary, Ramos-Montoya, Antonio, primary, Ross-Adams, Helen, primary, Visser, Matthieu, primary, Hoffmann, Ralf, primary, Ahmed, Ahmed Ashour, primary, Neal, David E., primary, and Mills, Ian G., primary

Published
2023
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22. Supplementary Table S1 from Salt-Inducible Kinase 2 Regulates Mitotic Progression and Transcription in Prostate Cancer

Author

Bon, Hélène, primary, Wadhwa, Karan, primary, Schreiner, Alexander, primary, Osborne, Michelle, primary, Carroll, Thomas, primary, Ramos-Montoya, Antonio, primary, Ross-Adams, Helen, primary, Visser, Matthieu, primary, Hoffmann, Ralf, primary, Ahmed, Ahmed Ashour, primary, Neal, David E., primary, and Mills, Ian G., primary

Published
2023
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23. Supplementary Figures 1-7 from Macrophage Activation Status Rather than Repolarization Is Associated with Enhanced Checkpoint Activity in Combination with PI3Kγ Inhibition

Author

Carnevalli, Larissa S., primary, Taylor, Molly A., primary, King, Matthew, primary, Coenen-Stass, Anna M.L., primary, Hughes, Adina M., primary, Bell, Sigourney, primary, Proia, Theresa A., primary, Wang, Yanjun, primary, Ramos-Montoya, Antonio, primary, Wali, Neha, primary, Carroll, Danielle, primary, Singh, Maneesh, primary, Moschetta, Michele, primary, Gutierrez, Pablo Morentin, primary, Gardelli, Cristina, primary, Critchlow, Susan E., primary, Klinowska, Teresa, primary, Fawell, Stephen E., primary, and Barry, Simon T., primary

Published
2023
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24. Data from Macrophage Activation Status Rather than Repolarization Is Associated with Enhanced Checkpoint Activity in Combination with PI3Kγ Inhibition

Author

Carnevalli, Larissa S., primary, Taylor, Molly A., primary, King, Matthew, primary, Coenen-Stass, Anna M.L., primary, Hughes, Adina M., primary, Bell, Sigourney, primary, Proia, Theresa A., primary, Wang, Yanjun, primary, Ramos-Montoya, Antonio, primary, Wali, Neha, primary, Carroll, Danielle, primary, Singh, Maneesh, primary, Moschetta, Michele, primary, Gutierrez, Pablo Morentin, primary, Gardelli, Cristina, primary, Critchlow, Susan E., primary, Klinowska, Teresa, primary, Fawell, Stephen E., primary, and Barry, Simon T., primary

Published
2023
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25. Supplementary Figure 8 from Salt-Inducible Kinase 2 Regulates Mitotic Progression and Transcription in Prostate Cancer

Author

Bon, Hélène, primary, Wadhwa, Karan, primary, Schreiner, Alexander, primary, Osborne, Michelle, primary, Carroll, Thomas, primary, Ramos-Montoya, Antonio, primary, Ross-Adams, Helen, primary, Visser, Matthieu, primary, Hoffmann, Ralf, primary, Ahmed, Ahmed Ashour, primary, Neal, David E., primary, and Mills, Ian G., primary

Published
2023
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26. Supplementary Data from The DNA-PK Inhibitor AZD7648 Sensitizes Patient-Derived Ovarian Cancer Xenografts to Pegylated Liposomal Doxorubicin and Olaparib Preventing Abdominal Metastases

Author

Anastasia, Alessia, primary, Dellavedova, Giulia, primary, Ramos-Montoya, Antonio, primary, James, Neil, primary, Chiorino, Giovanna, primary, Russo, Massimo, primary, Baakza, Hana, primary, Wilson, Joanne, primary, Ghilardi, Carmen, primary, Cadogan, Elaine B., primary, Giavazzi, Raffaella, primary, and Bani, Maria Rosa, primary

Published
2023
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27. Supplementary Figure Legend from Salt-Inducible Kinase 2 Regulates Mitotic Progression and Transcription in Prostate Cancer

Author

Bon, Hélène, primary, Wadhwa, Karan, primary, Schreiner, Alexander, primary, Osborne, Michelle, primary, Carroll, Thomas, primary, Ramos-Montoya, Antonio, primary, Ross-Adams, Helen, primary, Visser, Matthieu, primary, Hoffmann, Ralf, primary, Ahmed, Ahmed Ashour, primary, Neal, David E., primary, and Mills, Ian G., primary

Published
2023
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28. Supplementary Figure 3 from Salt-Inducible Kinase 2 Regulates Mitotic Progression and Transcription in Prostate Cancer

Author

Bon, Hélène, primary, Wadhwa, Karan, primary, Schreiner, Alexander, primary, Osborne, Michelle, primary, Carroll, Thomas, primary, Ramos-Montoya, Antonio, primary, Ross-Adams, Helen, primary, Visser, Matthieu, primary, Hoffmann, Ralf, primary, Ahmed, Ahmed Ashour, primary, Neal, David E., primary, and Mills, Ian G., primary

Published
2023
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29. Supplementary Figure 5 from Salt-Inducible Kinase 2 Regulates Mitotic Progression and Transcription in Prostate Cancer

Author

Bon, Hélène, primary, Wadhwa, Karan, primary, Schreiner, Alexander, primary, Osborne, Michelle, primary, Carroll, Thomas, primary, Ramos-Montoya, Antonio, primary, Ross-Adams, Helen, primary, Visser, Matthieu, primary, Hoffmann, Ralf, primary, Ahmed, Ahmed Ashour, primary, Neal, David E., primary, and Mills, Ian G., primary

Published
2023
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30. Supplementary Figure 4 from Salt-Inducible Kinase 2 Regulates Mitotic Progression and Transcription in Prostate Cancer

Author

Bon, Hélène, primary, Wadhwa, Karan, primary, Schreiner, Alexander, primary, Osborne, Michelle, primary, Carroll, Thomas, primary, Ramos-Montoya, Antonio, primary, Ross-Adams, Helen, primary, Visser, Matthieu, primary, Hoffmann, Ralf, primary, Ahmed, Ahmed Ashour, primary, Neal, David E., primary, and Mills, Ian G., primary

Published
2023
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31. Supplementary Figure 6 from Salt-Inducible Kinase 2 Regulates Mitotic Progression and Transcription in Prostate Cancer

Author

Bon, Hélène, primary, Wadhwa, Karan, primary, Schreiner, Alexander, primary, Osborne, Michelle, primary, Carroll, Thomas, primary, Ramos-Montoya, Antonio, primary, Ross-Adams, Helen, primary, Visser, Matthieu, primary, Hoffmann, Ralf, primary, Ahmed, Ahmed Ashour, primary, Neal, David E., primary, and Mills, Ian G., primary

Published
2023
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32. Supplementary Figure 7 from Salt-Inducible Kinase 2 Regulates Mitotic Progression and Transcription in Prostate Cancer

Author

Bon, Hélène, primary, Wadhwa, Karan, primary, Schreiner, Alexander, primary, Osborne, Michelle, primary, Carroll, Thomas, primary, Ramos-Montoya, Antonio, primary, Ross-Adams, Helen, primary, Visser, Matthieu, primary, Hoffmann, Ralf, primary, Ahmed, Ahmed Ashour, primary, Neal, David E., primary, and Mills, Ian G., primary

Published
2023
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33. Supplementary Figure 2 from Salt-Inducible Kinase 2 Regulates Mitotic Progression and Transcription in Prostate Cancer

Author

Bon, Hélène, primary, Wadhwa, Karan, primary, Schreiner, Alexander, primary, Osborne, Michelle, primary, Carroll, Thomas, primary, Ramos-Montoya, Antonio, primary, Ross-Adams, Helen, primary, Visser, Matthieu, primary, Hoffmann, Ralf, primary, Ahmed, Ahmed Ashour, primary, Neal, David E., primary, and Mills, Ian G., primary

Published
2023
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37. Supplementary Data from The DNA-PK Inhibitor AZD7648 Sensitizes Patient-Derived Ovarian Cancer Xenografts to Pegylated Liposomal Doxorubicin and Olaparib Preventing Abdominal Metastases

Author

Maria Rosa Bani, Raffaella Giavazzi, Elaine B. Cadogan, Carmen Ghilardi, Joanne Wilson, Hana Baakza, Massimo Russo, Giovanna Chiorino, Neil James, Antonio Ramos-Montoya, Giulia Dellavedova, and Alessia Anastasia

Abstract

Supplementary Data from The DNA-PK Inhibitor AZD7648 Sensitizes Patient-Derived Ovarian Cancer Xenografts to Pegylated Liposomal Doxorubicin and Olaparib Preventing Abdominal Metastases

Published
2023

39. Supplementary Table S1 from Salt-Inducible Kinase 2 Regulates Mitotic Progression and Transcription in Prostate Cancer

Author

Ian G. Mills, David E. Neal, Ahmed Ashour Ahmed, Ralf Hoffmann, Matthieu Visser, Helen Ross-Adams, Antonio Ramos-Montoya, Thomas Carroll, Michelle Osborne, Alexander Schreiner, Karan Wadhwa, and Hélène Bon

Abstract

Supplementary Table S1. qRT-PCR primer sequences. When primer sequences were not from published studies, they were designed using Integrated DNA Technologies software.

Published
2023

40. Data from The DNA-PK Inhibitor AZD7648 Sensitizes Patient-Derived Ovarian Cancer Xenografts to Pegylated Liposomal Doxorubicin and Olaparib Preventing Abdominal Metastases

Author

Maria Rosa Bani, Raffaella Giavazzi, Elaine B. Cadogan, Carmen Ghilardi, Joanne Wilson, Hana Baakza, Massimo Russo, Giovanna Chiorino, Neil James, Antonio Ramos-Montoya, Giulia Dellavedova, and Alessia Anastasia

Abstract

Ovarian cancer is the deadliest gynecologic cancer, with a 5-year survival rate of 30%, when the disease has spread throughout the peritoneal cavity.We investigated the efficacy to delay disease progression by the DNA-dependent protein kinase (DNA-PK) inhibitor AZD7648, administered in combination with two of the therapeutic options for patient management: either pegylated liposomal doxorubicin (PLD) or the PARP inhibitor olaparib. Patient-derived ovarian cancer xenografts (OC-PDX) were transplanted subcutaneously to evaluate the effect of treatment on tumor growth, or orthotopically in the peritoneal cavity to evaluate the effect on metastatic spread. AZD7648 was administered orally in combination with PLD (dosed intravenously) or with olaparib (orally). To prove the inhibition of DNA-PK in the tumors, we measured pDNA-PKcs, pRPA32, and γH2AX, biomarkers of DNA-PK activity.AZD7648 enhanced the therapeutic efficacy of PLD in all the OC-PDXs tested, regardless of their BRCA status or sensitivity to cisplatin or PLD. The treatment caused disease stabilization, which persisted despite therapy discontinuation for tumors growing subcutaneously, and significantly impaired the abdominal metastatic dissemination, prolonging the lifespan of mice implanted orthotopically.AZD7648 potentiated the efficacy of olaparib in BRCA-deficient OC-PDXs but did not sensitize BRCA-proficient OC-PDXs to olaparib, despite an equivalent inhibition of DNA-PK, suggesting the need of a preexisting olaparib activity to benefit from the addition of AZD7648.This work suggests that AZD7648, an inhibitor of DNA-PK, dosed in combination with PLD or olaparib is an exciting therapeutic option that could benefit patients with ovarian cancer and should be explored in clinical trials.

Published
2023

42. Data from Macrophage Activation Status Rather than Repolarization Is Associated with Enhanced Checkpoint Activity in Combination with PI3Kγ Inhibition

Author

Simon T. Barry, Stephen E. Fawell, Teresa Klinowska, Susan E. Critchlow, Cristina Gardelli, Pablo Morentin Gutierrez, Michele Moschetta, Maneesh Singh, Danielle Carroll, Neha Wali, Antonio Ramos-Montoya, Yanjun Wang, Theresa A. Proia, Sigourney Bell, Adina M. Hughes, Anna M.L. Coenen-Stass, Matthew King, Molly A. Taylor, and Larissa S. Carnevalli

Abstract

Suppressive myeloid cells mediate resistance to immune checkpoint blockade. PI3Kγ inhibition can target suppressive macrophages, and enhance efficacy of immune checkpoint inhibitors. However, how PI3Kγ inhibitors function in different tumor microenvironments (TME) to activate specific immune cells is underexplored. The effect of the novel PI3Kγ inhibitor AZD3458 was assessed in preclinical models. AZD3458 enhanced antitumor activity of immune checkpoint inhibitors in 4T1, CT26, and MC38 syngeneic models, increasing CD8+ T-cell activation status. Immune and TME biomarker analysis of MC38 tumors revealed that AZD3458 monotherapy or combination treatment did not repolarize the phenotype of tumor-associated macrophage cells but induced gene signatures associated with LPS and type II INF activation. The activation biomarkers were present across tumor macrophages that appear phenotypically heterogenous. AZD3458 alone or in combination with PD-1–blocking antibodies promoted an increase in antigen-presenting (MHCII+) and cytotoxic (iNOS+)-activated macrophages, as well as dendritic cell activation. AZD3458 reduced IL-10 secretion and signaling in primary human macrophages and murine tumor-associated macrophages, but did not strongly regulate IL-12 as observed in other studies. Therefore, rather than polarizing tumor macrophages, PI3Kγ inhibition with AZD3458 promotes a cytotoxic switch of macrophages into antigen-presenting activated macrophages, resulting in CD8 T-cell–mediated antitumor activity with immune checkpoint inhibitors associated with tumor and peripheral immune activation.

Published
2023

43. Supplementary Figures 1-7 from Macrophage Activation Status Rather than Repolarization Is Associated with Enhanced Checkpoint Activity in Combination with PI3Kγ Inhibition

Author

Simon T. Barry, Stephen E. Fawell, Teresa Klinowska, Susan E. Critchlow, Cristina Gardelli, Pablo Morentin Gutierrez, Michele Moschetta, Maneesh Singh, Danielle Carroll, Neha Wali, Antonio Ramos-Montoya, Yanjun Wang, Theresa A. Proia, Sigourney Bell, Adina M. Hughes, Anna M.L. Coenen-Stass, Matthew King, Molly A. Taylor, and Larissa S. Carnevalli

Abstract

Supplementary Figure 1. Pharmacokinetic (PK) properties of AZD3458 in mouse. Supplementary Figure 2. In vivo pharmacodynamic properties of AZD3458 in mouse neutrophils. Supp Fig 3. PI3K-�/mTOR pathway regulates expression of IL-10/IL-12 via LPS-induced glycolytic burst. Supplementary Figure 4. AZD3458 improves checkpoint activity in CT-26 tumor models. Supplementary Figure 5. AZD3458 improves checkpoint activity in 4T1 tumor models. Supplementary Figure 6. Top canonical IPA pathways across tissues in AZD3458+PD-1 combination group. Supplementary Figure 7. Graphical abstract.

Published
2023

44. Supplementary Figure 6 from Salt-Inducible Kinase 2 Regulates Mitotic Progression and Transcription in Prostate Cancer

Author

Ian G. Mills, David E. Neal, Ahmed Ashour Ahmed, Ralf Hoffmann, Matthieu Visser, Helen Ross-Adams, Antonio Ramos-Montoya, Thomas Carroll, Michelle Osborne, Alexander Schreiner, Karan Wadhwa, and Hélène Bon

Abstract

Supplementary Figure 6 (Relates to Figure 5) - SIK2 regulates CREB1 activity via the phosphorylation of TORC2 and TORC3 and their sequestration in the cytoplasm.

Published
2023

46. Supplementary Materials and Methods and Supplementary Tables 1-2 from Macrophage Activation Status Rather than Repolarization Is Associated with Enhanced Checkpoint Activity in Combination with PI3Kγ Inhibition

Author

Simon T. Barry, Stephen E. Fawell, Teresa Klinowska, Susan E. Critchlow, Cristina Gardelli, Pablo Morentin Gutierrez, Michele Moschetta, Maneesh Singh, Danielle Carroll, Neha Wali, Antonio Ramos-Montoya, Yanjun Wang, Theresa A. Proia, Sigourney Bell, Adina M. Hughes, Anna M.L. Coenen-Stass, Matthew King, Molly A. Taylor, and Larissa S. Carnevalli

Abstract

Supplementary Materials and Methods. Suplementary Table 1. Tumor Immuno-phenotyping. Suplementary Table 2. Flow cytometry panels.

Published
2023

48. Supplementary Figure 3 from Salt-Inducible Kinase 2 Regulates Mitotic Progression and Transcription in Prostate Cancer

Author

Ian G. Mills, David E. Neal, Ahmed Ashour Ahmed, Ralf Hoffmann, Matthieu Visser, Helen Ross-Adams, Antonio Ramos-Montoya, Thomas Carroll, Michelle Osborne, Alexander Schreiner, Karan Wadhwa, and Hélène Bon

Abstract

Supplementary Figure 3 (Relates to Figure 4) - SIK2 knock-down induces a cell cycle arrest in G1 phase and delays mitotic progression of LNCaP cells.

Published
2023

50. AZD7648 is a potent and selective DNA-PK inhibitor that enhances radiation, chemotherapy and olaparib activity

Author

Fok, Jacqueline H. L., Ramos-Montoya, Antonio, Vazquez-Chantada, Mercedes, Wijnhoven, Paul W. G., Follia, Valeria, James, Neil, Farrington, Paul M., Karmokar, Ankur, Willis, Sophie E., Cairns, Jonathan, Nikkilä, Jenni, Beattie, David, Lamont, Gillian M., Finlay, M. Raymond V., Wilson, Joanne, Smith, Aaron, O’Connor, Lenka Oplustil, Ling, Stephanie, Fawell, Stephen E., O’Connor, Mark J., Hollingsworth, Simon J., Dean, Emma, Goldberg, Frederick W., Davies, Barry R., and Cadogan, Elaine B.

Published
2019
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