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

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...

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Autores principales:	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, Raffaella Giavazzi
Formato:	article
Lenguaje:	EN
Publicado:	BMC 2021
Materias:	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
Acceso en línea:	https://doaj.org/article/5d13984571584daaa1864d9ef2ed329a
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spelling	oai:doaj.org-article:5d13984571584daaa1864d9ef2ed329a2021-11-07T12:02:54ZVEGF pathway inhibition potentiates PARP inhibitor efficacy in ovarian cancer independent of BRCA status10.1186/s13045-021-01196-x1756-8722https://doaj.org/article/5d13984571584daaa1864d9ef2ed329a2021-11-01T00:00:00Zhttps://doi.org/10.1186/s13045-021-01196-xhttps://doaj.org/toc/1756-8722Abstract 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.Francesca BizzaroIlaria Fuso NeriniMolly A. TaylorAlessia AnastasiaMassimo RussoGiovanna DamiaFederica GuffantiFrancesca GuanaPaola OstanoLucia MinoliMaureen M. HattersleyStephanie ArnoldAntonio Ramos-MontoyaStuart C. WilliamsonAlessandro GalbiatiJelena UrosevicElisabetta LeoUgo CavallaroCarmen GhilardiSimon T. BarryMaria Rosa BaniRaffaella GiavazziBMCarticleOvarian cancerPatient-derived xenograftPARP inhibitorVEGF pathway inhibitorBRCAOlaparibDiseases of the blood and blood-forming organsRC633-647.5Neoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENJournal of Hematology & Oncology, Vol 14, Iss 1, Pp 1-7 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	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
spellingShingle	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 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 Raffaella Giavazzi VEGF pathway inhibition potentiates PARP inhibitor efficacy in ovarian cancer independent of BRCA status
description	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.
format	article
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 Raffaella Giavazzi
author_facet	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 Raffaella Giavazzi
author_sort	Francesca Bizzaro
title	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_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_sort	vegf pathway inhibition potentiates parp inhibitor efficacy in ovarian cancer independent of brca status
publisher	BMC
publishDate	2021
url	https://doaj.org/article/5d13984571584daaa1864d9ef2ed329a
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VEGF pathway inhibition potentiates PARP inhibitor efficacy in ovarian cancer independent of BRCA status

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