Journal Article

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

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

2021

Overview

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.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Analysis / Animals / Antineoplastic Agents - therapeutic use / BRCA / Breast cancer / Cancer / Cancer Research / Care and treatment / Cell Line, Tumor / Development and progression / DNA repair / Drug therapy / Female / Genes, BRCA1 - drug effects / Genes, BRCA2 - drug effects / Hematology / Homologous recombination / Homologous recombination repair / Humans / Kinases / Letter to the Editor / Medicine / Medicine & Public Health / Mice / Mice, Nude / Microenvironments / Monosaccharides / Olaparib / Oncology / Ovarian cancer / Ovarian Neoplasms - drug therapy / Ovarian Neoplasms - genetics / Ovarian Neoplasms - metabolism / PARP inhibitor / Patient-derived xenograft / Patients / Phthalazines - therapeutic use / Piperazines - therapeutic use / Poly(ADP-ribose) polymerase / Poly(ADP-ribose) Polymerase Inhibitors - therapeutic use / Quinazolines - therapeutic use / Ribose / Signal transduction / Signal Transduction - drug effects / Sugars / Tumor Microenvironment - drug effects / Tumors / Tyrosine / Vascular endothelial growth factor / Vascular Endothelial Growth Factor A - antagonists & inhibitors / Vascular Endothelial Growth Factor A - metabolism / Vascular endothelial growth factor receptors / VEGF pathway inhibitor / Xenografts