Abstract
Niraparib is an orally bioavailable and selective poly (ADP-ribose) polymerase (PARP)-1/-2 inhibitor approved for maintenance treatment of both BRCA mutant (mut) and BRCA wildtype (wt) adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancers who have demonstrated a complete or partial response to platinum-based chemotherapy. In patients without germline BRCA mutations (non-gBRCAmut), niraparib improved progression-free survival (PFS) by 5.4 months, whereas another PARP inhibitor (PARPi) olaparib supplied only 1.9 months of improvement in a similar patient population. Previous studies revealed higher cell membrane permeability and volume of distribution (VD) as unique features of niraparib in comparison to other PARPi including olaparib. Here, we explore the potential correlation of these pharmacokinetic properties to preclinical antitumor effects in BRCAwt tumors. Our results show that at steady state, tumor exposure to niraparib is 3.3 times greater than plasma exposure in tumor xenograft mouse models. In comparison, the tumor exposure to olaparib is less than observed in plasma. In addition, niraparib crosses the blood-brain barrier and shows good sustainability in the brain, whereas sustained brain exposure to olaparib is not observed in the same models. Consistent with its favorable tumor and brain distribution, niraparib achieves more potent tumor growth inhibition than olaparib in BRCAwt models and an intracranial tumor model at maximum tolerated doses (MTD). These findings demonstrate favorable pharmacokinetic profiles and potent antitumor effects of niraparib in BRCAwt tumors, consistent with its broader clinical effect in patients with both BRCAmut and BRCAwt tumors.
Highlights
PARP1 and 2 are key enzymes acting as DNA damage sensors and signal transducers in response to DNA damage
Brain, bone marrow, muscle, and plasma exposure to niraparib and olaparib were measured in samples collected from NOD/SCID mice orthotopically inoculated with BRCA1mut MDA-MB-436 triple-negative breast cancer (TNBC) cells and treated with 75 mg/kg of niraparib once daily or olaparib (100 mg/kg qd) for 5 days
Tissue and plasma exposure to niraparib and olaparib were measured in samples collected from BALB/c nude mice subcutaneously implanted with the BRCAwt OVC134 ovarian tumor fragment and treated with niraparib (50 mg/ kg qd) or 67 mg/kg of olaparib twice a day for 2 days at maximum tolerated doses (MTD) previously determined in this model
Summary
PARP1 and 2 are key enzymes acting as DNA damage sensors and signal transducers in response to DNA damage. Consistent with the importance of PARP in DNA repair, inhibition of PARP activity in homologous recombination (HR)deficient cells (such as those with BRCA and PALB2 mutations) induces cell death due to a mechanism known as ‘synthetic lethality’, as it is difficult for cancer cells to tolerate simultaneous loss of both PARP-dependent www.oncotarget.com. SSB repair and HR-mediated double-strand break (DSB) repair machinery This important observation led to the pharmaceutical development of PARP inhibitors (PARPi) [5,6,7]. 40-50% of HGSOC have some level of genetic or epigenetic alterations in HR repair pathways including mutations in BRCA1/2, Fanconi anemia genes, core HR genes, DNA damage response genes and epigenetic silencing of BRCA1 via promoter hypermethylation [9,10,11,12,13,14,15,16]. Murai and colleagues showed that BRCA1/2 or XRCC2/3 mutant cells are more sensitive to PARPi treatment in vitro than RAD54, FANCC, or POLH/Z mutant cells by 1 to 2 orders of magnitude [22], indicating that for a PARPi to be efficacious, higher concentration of drug is required in BRCAwt than BRCAmut tumors
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