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 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.

Combinations of ATR, Chk1 and Wee1 Inhibitors with Olaparib Are Active in Olaparib Resistant Brca1 Proficient and Deficient Murine Ovarian Cells

“…According to the Cancer Genome Atlas (TCGA) consortium, more than half of HGSOC have homologous recombination (HR) deficiency due to mutations in genes involved in this pathway, including BRCA1 and 2 [ 7 ]. The synthetic lethality between HR deficiency and PARP inhibition [ 8 , 9 ] is at the basis of the strong antitumor activity of PARPi in HR-deficient tumors [ 10 , 11 ]. PARP enzymes catalyze the addition of poly(ADP-ribose) adducts to target proteins involved in cell signaling and DNA damage response, and their inhibition leads to accumulation of DNA single strand breaks (SSBs) and to a stall of replication forks, eventually progressing to double strand breaks (DSBs), which are highly cytotoxic to cells lacking a proficient HR [ 12 ].…”

Randomized phase II trial of weekly paclitaxel vs. cediranib-olaparib (continuous or intermittent schedule) in platinum-resistant high-grade epithelial ovarian cancer

“…On the biological basis, the synergistic effect of cediranib-olaparib seems to be due to the down-regulation of some genes involved in the homologous recombination system induced by cediranib which, in turn, potentiate the effect of olaparib [12]. Recent findings from patient-derived ovarian cancer xenografts confirmed an additive combination benefit in tumors poorly-sensitive to platinum and olaparib although this combination effect was mostly driven by targeting independent mechanisms [13].…”

A Novel PARP Inhibitor YHP-836 For the Treatment of BRCA-Deficiency Cancers

“…In addition to monotherapy for cancers with HRD, PARP inhibitors are under clinical assessment in combination with other antitumor agents referred for chemotherapy, targeted therapy, and immunotherapy ( Plummer et al, 2013 ; Norris et al, 2014 ; Matulonis and Monk, 2017 ; Tomao et al, 2017 ; Friedlander et al, 2019 ; Lee and Konstantinopoulos, 2019 ; Lampert et al, 2020 ; Palaia et al, 2020 ; Bizzaro et al, 2021 ; Waddington et al, 2021 ). Similar to other PARP inhibitors, YHP-836 also potentiates chemotherapy agents against various tumor cells.…”

“…PARP inhibitors, including olaparib, rucaparib, niraparib, talazoparib, and pamiparib, have clinically demonstrated significant and sustained antitumor responses as a single agent in patients with gBRCA mutation tumors with a favorable toxicity profile ( Brown et al, 2016 ; Spriggs and Longo, 2016 ; Yuan et al, 2017 ; Mateo et al, 2019 ; Markham, 2021 ; Paluch-Shimon and Cardoso, 2021 ). PARP inhibitors have also been shown to sensitize tumors cells with chemotherapy drugs such as alkylating agents, topoisomerase I inhibitors, and anti-angiogenesis agents ( Plummer et al, 2013 ; Norris et al, 2014 ; Ivy et al, 2016 ; Matulonis and Monk, 2017 ; Lu et al, 2018 ; Bizzaro et al, 2021 ; Chatterjee et al, 2021 ). Recently, PARP1/2 inhibitors have been reported to be involved in cancer immunity via various mechanisms ( Lee and Konstantinopoulos, 2019 ; Lampert et al, 2020 ; Lee and Konstantinopoulos, 2020 ).…”