Pamiparib is a potent and selective PARP inhibitor with unique potential for the treatment of brain tumor

Abstract

Pamiparib, an investigational Poly (ADP-ribose) polymerase (PARP) inhibitor in clinical development, demonstrates excellent selectivity for both PARP1 and PARP2, and superb anti-proliferation activities in tumor cell lines with BRCA1/2 mutations or HR pathway deficiency (HRD). Pamiparib has good bioavailability and is 16-fold more potent than olaparib in an efficacy study using BRCA1 mutated MDA-MB-436 breast cancer xenograft model. Pamiparib also shows strong anti-tumor synergy with temozolomide (TMZ), a DNA alkylating agent used to treat brain tumors. Compared to other PARP inhibitors, pamiparib demonstrated improved penetration across the blood brain barrier (BBB) in mice. Oral administration of pamiparib at a dose as low as 3 mg/kg is sufficient to abrogate PARylation in brain tumor tissues. In SCLC-derived, TMZ-resistant H209 intracranial xenograft model, combination of pamiparib with TMZ overcomes its resistance and shows significant tumor inhibitory effects and prolonged life span. Our data suggests that combination of pamiparib with TMZ has unique potential for treatment of brain tumors. Currently, the combination therapy of pamiparib with TMZ is evaluated in clinical trial [NCT03150862].

Keywords: Brain penetration; PARP; Pamiparib; TMZ.

Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.

Figures

Fig. 1

The structural of Pamiparib and its activity. (A) The chemical structure of pamiparib. (B) The inhibitory effect of pamiparib on PARP enzymes. (C) The efficacy of pamiparib against intracellular PAR levels in HeLa cells. HeLa cells were incubated with the indicated concentrations of pamiparib for 18 hrs, and then cells were exposed to hydrogen peroxide (H2O2) to induce PAR synthesis. PAR levels without H2O2 induction were set as 100%.

Fig. 2

Pamiparib shows specific growth inhibitory effects in HR deficient and BRAC mutant cell lines. (A) The anti-proliferative activity of pamiparib in several tumor cell lines. IC50 values indicate that pamiparib potently inhibited the tumor cells with HR-deficiency or BRAC mutants. For all experiments, viability was derived after 7 days of continuous treatment with pamiparib.

Fig. 3

In vivo efficacy, PK and PD of pamiparib in a human MDA-MB-436 breast cancer xenograft model. (A) In vivo efficacy of pamiparib and olaparib was head-to-head compared in a human MDA-MB-436 breast cancer xenograft model. Doses ranging from 1.6 mg/kg to 12.5 mg/kg of pamiparib and 25 mg/kg, 50 mg/kg olaparib (oral, BID for 28 days) were tested in this model. Pamiparib induced tumor regression on day 29 and resulted in 100% objective responses (PR plus CR). At day 89, two months after treatment was terminated, tumor relapse was observed only in the lowest dose group (1.6 mg/kg); (B) all treatments had no effect on mouse body weight. (C) Dose-dependence of tumor PARylation inhibition and pamiparib plasma/tumor concentrations in the same model. Pamiparib induced a dose-dependent inhibition of PAR levels by 4 h after single oral administration of 0.17–10.9 mg/kg, which was correlated well with its PK in tumors; (D) time-dependence of PAR inhibition in tumors and its correlation with plasma/tumor PK. A single dose of 5.45 mg/kg pamiparib induced a rapid and potent decrease in PAR levels. The PARylation inhibition was 98% at 0.5 h and remained high (≥80%) throughout the first 12 h; at 24 h post treatment, the inhibition remained at 53%. (E) The PARylation inhibited by pamiparib and olaparib were compared head-to-head. Compared to olaparib, pamiparib induced a more sustained PAR inhibition.

Fig. 4

Pamiparib potentiates temozolomide in both naive and TMZ-resistant H209 cells and in a xenograft mouse model. (A and B) IC50 curves in H209 and H209 TMZ resistance (H209-TR) cell lines. H209-TR cell lines were generated from H209 tumors by treatment with multiple cycles of TMZ in vivo. The derived H209-TR cells remained sensitive to the combination of pamiparib and TMZ in vitro. (C) The combined activity of pamiparib and TMZ in the H209 SCLC xenograft model. TMZ as a single agent was quite effective in this H209 model. One cycle of treatment resulted in all animals becoming tumor-free. However, resistance occurred quickly during the second cycle. Pamiparib and TMZ together significantly prevented resistance, and tumors remained sensitive to the drug combination after three cycles of 5-day treatment. (D) Synergistic activity of pamiparib and TMZ in the H209-TR xenograft model. TMZ single treatment was not effective in this model. In contrast, pamiparib and TMZ combination treatment was efficacious during two cycles of treatment.

Fig. 5

Brain penetration of pamiparib and its efficacy combined with TMZ in an intracranial H209 xenograft model. (A) Brain penetration of pamiparib in an intracranial H209 xenograft at 1.5 mg/kg p.o. (B) PD activity of pamiparib in the intracranial model, PARylation in brain/tumor was completely inhibited at 4 h after a single dose of 3 mpk p.o. (C and D) The synergistic activity of pamiparib and TMZ in H209 and H209-TR intracranial xenograft. TMZ and the combination treatment of TMZ and pamiparib showed no significant difference in survival in the H209 naïve model. However, the combination treatment of TMZ and pamiparib dramatically prolonged the survival of the H209-TR models. The survival time was defined as the time from the day of tumor cell inoculation to one day before animal death or euthanization. Kaplan–Meier curves were generated using mouse survival duration in days.