Beyond Breast and Ovarian Cancers: PARP Inhibitors for BRCA Mutation-Associated and BRCA-Like Solid Tumors

Abstract

Poly(ADP-ribose) polymerase inhibitors (PARPi) have shown clinical activity in patients with germline BRCA1/2 mutation (gBRCAm)-associated breast and ovarian cancers. Accumulating evidence suggests that PARPi may have a wider application in the treatment of cancers defective in DNA damage repair pathways, such as prostate, lung, endometrial, and pancreatic cancers. Several PARPi are currently in phase I/II clinical investigation, as single-agents and/or combination therapy in these solid tumors. Understanding more about the molecular abnormalities involved in BRCA-like phenotype in solid tumors beyond breast and ovarian cancers, exploring novel therapeutic trial strategies and drug combinations, and defining potential predictive biomarkers are critical to expanding the scope of PARPi therapy. This will improve clinical outcome in advanced solid tumors. Here, we briefly review the preclinical data and clinical development of PARPi, and discuss its future development in solid tumors beyond gBRCAm-associated breast and ovarian cancers.

The role of poly(ADP-ribose) polymerase inhibitors in the treatment of endometrial cancer: a scoping review of the current literature

“…Of the studies selected for analysis, 4 were in vitro [14,[32][33][34], 2 were in vivo [35,36], 6 were reviews [3,7,[37][38][39][40], and 5 were clinical trials.…”

“…Several review articles [7,37,38] noted that in addition to the promising role PARP inhibitors may play in the treatment of BRCA mutation-associated breast and ovarian cancer, these drugs may have a wider application in the treatment of cancers with defective DNA damage repair pathways other than BRCA mutations. Other reviews [3,39,40] commented on the promising results of recent studies and those underway at the time of publication, but noted that further clinical evaluation of the potential utility of PARP inhibitors in the treatment of endometrial cancer is needed.…”

Molecular landscape of prostate cancer: Implications for current clinical trials

“…DNA repair genes such as BRCA2 and ATM are also altered in prostate cancer (with a subset of patients having germline mutations). PARP inhibitors and platinums can effectively target these abnormalities in several cancers, and merit further exploration in BRCA2-and ATM-aberrant prostate cancer [33,105]. Despite the number of aberrations that can be targeted, relatively few have been addressed in clinical trials of prostate cancer, with only 2.0% of clinical trials (posted on clinicaltrials.gov in the last 3 years; September 1, 2011, through September 1, 2014) employing a biomarker-based patient selection strategy.…”

Embracing synthetic lethality of novel anticancer therapies

“…In addition, some other SL pairs are involved in regulation of apoptosis and other metabolic pathways [24][25][26]. In DNA repair, the PARP1 class of protein is significantly involved in base excision repair (BER) as well as in homologous recombination (HR) repair by activating x-ray repair cross-complementing protein (XRCC1) and ataxia telangiectasia mutated (ATM), respectively; however, it inhibits non-homologous end-joining (NHEJ) by inactivating DNA-dependent protein kinase catalytic subunit (DNA-PKcs) [27,28]. Various inhibitors of PARP blocks Article highlights.…”