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VEGF pathway inhibition potentiates PARP inhibitor efficacy in ovarian cancer independent of BRCA status

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 inhi...

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Autores principales: 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, Giavazzi, Raffaella
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8572452/
https://www.ncbi.nlm.nih.gov/pubmed/34742344
http://dx.doi.org/10.1186/s13045-021-01196-x
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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
Giavazzi, Raffaella
author_facet 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
Giavazzi, Raffaella
author_sort Bizzaro, Francesca
collection PubMed
description 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13045-021-01196-x.
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spelling pubmed-85724522021-11-08 VEGF pathway inhibition potentiates PARP inhibitor efficacy in ovarian cancer independent of BRCA status 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 Giavazzi, Raffaella J Hematol Oncol Letter to the Editor 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13045-021-01196-x. BioMed Central 2021-11-06 /pmc/articles/PMC8572452/ /pubmed/34742344 http://dx.doi.org/10.1186/s13045-021-01196-x Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Letter to the Editor
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
Giavazzi, Raffaella
VEGF pathway inhibition potentiates PARP inhibitor efficacy in ovarian cancer independent of BRCA status
title VEGF pathway inhibition potentiates PARP inhibitor efficacy in ovarian cancer independent of BRCA status
title_full VEGF pathway inhibition potentiates PARP inhibitor efficacy in ovarian cancer independent of BRCA status
title_fullStr VEGF pathway inhibition potentiates PARP inhibitor efficacy in ovarian cancer independent of BRCA status
title_full_unstemmed VEGF pathway inhibition potentiates PARP inhibitor efficacy in ovarian cancer independent of BRCA status
title_short VEGF pathway inhibition potentiates PARP inhibitor efficacy in ovarian cancer independent of BRCA status
title_sort vegf pathway inhibition potentiates parp inhibitor efficacy in ovarian cancer independent of brca status
topic Letter to the Editor
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8572452/
https://www.ncbi.nlm.nih.gov/pubmed/34742344
http://dx.doi.org/10.1186/s13045-021-01196-x
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