PARP Inhibitors

Abstract

Poly (ADP-ribose) polymerase (PARP) is a novel therapeutic target in cancer. Preclinical studies demonstrate that PARP inhibitors selectively kill BRCAdeficient cells and potentiate the effects of DNA-damaging agents. There are several PARP inhibitors in clinical development, including olaparib, iniparib, veliparib, PF-01367338, and MK-4827. Phase II studies of single-agent olaparib demonstrate activity in BRCA-associated cancers. A randomized phase II trial showed that the addition of iniparib to gemcitabine and carboplatin in patients with metastatic triple-negative breast cancer (TNBC) improved progression-free survival and overall survival. A phase III trial evaluating this combination in metastatic TNBC has completed accrual. Phase III studies of olaparib in BRCAassociated breast cancer and veliparib in breast cancer are being planned. This article reviews the clinical studies to date that have evaluated PARP inhibitors as a single agent or in combination with chemotherapy in patients with breast cancer, including BRCA-associated breast cancer and TNBC.

Cross-platform pathway-based analysis identifies markers of response to the PARP inhibitor olaparib

“…PARP is involved in SSB DNA repair and PARP inhibitors cause some of them to be converted into DSBs at replication forks [ 13 , 14 ]. In HR competent cells, DSBs are repaired so that the cells can survive.…”

“…PARP inhibitors in clinical studies for BRCA-associated, triple negative and/or basal-like breast cancer include olaparib (AstraZeneca, London), ABT-888 (also known as Veliparib; Abbott Laboratories, IL), and PF-01367338 (AG014699; Pfizer Inc., NY) [ 14 , 18 , 19 ]. These agents are licensed for monotherapy in DNA repair deficient patients or as chemo-potentiating agents after SSBs are created by common anticancer treatments such as radiotherapy and DNA damaging agents [ 19 ].…”

Targeted drugs and diagnostic assays Companions in the race to combat ethnic disparity

“…Although no clinically validated methods of selecting patients most likely to exhibit a robust response to PARP-1 inhibitors exist, standard BRCA genetic mutation screening routinely conducted in clinics may suffice for predicting a significant response in AA breast cancer patients. Discoveries of biomarkers that can predict patient response may impart insights into sensitivity of AA breast cancer patients to PARP inhibitors (35).…”

Poly(ADP-Ribose) Polymerase Inhibitors (PARPi) for Patients With Advanced Breast Cancer: a Meta-analysis of Randomized Controlled Trials

“…Breast tumor is the most popular female malignancy, with an estimated 1 million new cases diagnosed in 2012 (a quarter of all cancers [1].In 2016, there were approximately 246 660 women diagnosed with breast tumor within America. Recent decades have shown signi cant progress with the therapy of breast tumor.…”

“…Recent decades have shown signi cant progress with the therapy of breast tumor. Human epidermal growth factor receptor type 2 (HER2)-targeted therapies and Endocrine treatment have received a substantial improvement in overall survival(OS) in patients with HER2-positive and hormone receptor(HR) positive breast tumor [1]. Despite extensive research, triple-negative (estrogen receptor (ER),progesterone receptor (PR) negative,and HER2-negative) breast cancers (TNBC), still lack speci c methods for therapy [3].At present, the mainstay of treatment for triple-negative breast cancer and BRCA associated triple-negative is still chemotherapy.…”