in vi·vo:
(of a process) performed or taking place in a living organism. ```````````````
abstract
OBJECTIVE:
Poly(ADP-ribose)
polymerase (PARP) inhibitors have yielded encouraging responses in
high-grade serous ovarian carcinomas (HGSOCs), but the optimal treatment
setting remains unknown. We assessed the effect of niraparib on HGSOC
patient-derived xenograft (PDX) models as well as the relationship
between certain markers of homologous recombination (HR) status,
including
BRCA1/2 mutations and formation of RAD51 foci after DNA
damage, and response of these PDXs to
niraparib in vivo.
METHODS:
Massively
parallel sequencing was performed on HGSOCs to identify mutations
contributing to HR deficiency. HR pathway integrity was assessed using
fluorescence microscopy-based RAD51 focus formation assays. Effects of
niraparib (MK-4827) on treatment-naïve PDX tumor growth as monotherapy,
in combination with carboplatin/paclitaxel, and as maintenance therapy
were assessed by transabdominal ultrasound. Niraparib responses were
correlated with changes in levels of poly(ADP-ribose), PARP1, and repair
proteins by western blotting.
RESULTS:
Five
PDX models were evaluated in vivo. Tumor regressions were induced by
single-agent niraparib in one of two PDX models with deleterious BRCA2
mutations and in a PDX with RAD51C promoter methylation. Diminished
formation of RAD51 foci failed to predict response, but Artemis loss was
associated with resistance.
Niraparib generally failed to enhance
responses to carboplatin/paclitaxel chemotherapy, but maintenance
niraparib therapy delayed progression in a BRCA2-deficient PDX.
CONCLUSIONS:
Mutations
in HR genes are neither necessary nor sufficient to predict response to
niraparib. Assessment of repair status through multiple complementary
assays is needed to guide PARP inhibitor therapy, design future clinical
trials and identify ovarian cancer patients most likely to benefit from
PARP inhibition.
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