Pamiparib is a Potent and Selective PARP Inhibitor with Unique Potential for the Treatment of Brain Tumor

Overview

Journal Neoplasia

Publisher Elsevier

Specialty Oncology

Date 2020 Jul 12

PMID 32652442

Citations 45

Authors

Yao Xiong

Yin Guo

Ye Liu

Hexiang Wang

Wenfeng Gong

Yong Liu

Xing Wang

Yajuan Gao

Fenglong Yu

Dan Su

Fan Wang

Yutong Zhu

Yuan Zhao

Yiyuan Wu

Zhen Qin

Xuebing Sun

Bo Ren

Bin Jiang

Wei Jin

Zhirong Shen

Zhiyu Tang

Xiaomin Song

Lai Wang

Xuesong Liu

Changyou Zhou

Beibei Jiang

Affiliations

Soon will be listed here.

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].

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