Format

Send to

Choose Destination
Diagnostics (Basel). 2019 Aug 1;9(3). pii: E87. doi: 10.3390/diagnostics9030087.

Combined Strategies with Poly (ADP-Ribose) Polymerase (PARP) Inhibitors for the Treatment of Ovarian Cancer: A Literature Review.

Author information

1
Acute Oncology Assessment Unit, Medway NHS Foundation Trust, Windmill Road, Gillingham ME7 5NY, Kent, UK. stergiosboussios@gmail.com.
2
AELIA Organization, 9th Km Thessaloniki-Thermi, 57001 Thessaloniki, Greece. stergiosboussios@gmail.com.
3
Department of Oncology and Radiotherapy, Medical Research Center Oulu, Oulu University Hospital and University of Oulu, P.O. Box 22, 90029 Oulu, Finland.
4
Drug Development Unit, Sarah Cannon Research Institute, 93 Harley Street, London W1G 6AD, UK.
5
Acute Oncology Assessment Unit, Medway NHS Foundation Trust, Windmill Road, Gillingham ME7 5NY, Kent, UK.
6
Department of Pharmacy, Medway NHS Foundation Trust, Windmill Road, Gillingham ME7 5NY, Kent, UK.
7
Department of Cancer Medicine, Gustave Roussy Institut, 94805 Villejuif, France.
8
Department of Hematology-Oncology, Hotel Dieu de France University Hospital, Faculty of Medicine, Saint Joseph University, 166830 Beirut, Lebanon.
9
Medical School, University of Ioannina, Stavros Niarchou Avenue, 45110 Ioannina, Greece.

Abstract

Poly (ADP-ribose) polymerase (PARP) inhibitors are the first clinically approved drugs designed to exploit synthetic lethality, and were first introduced as a cancer-targeting strategy in 2005. They have led to a major change in the treatment of advanced ovarian cancer, and altered the natural history of a disease with extreme genetic complexity and defective DNA repair via homologous recombination (HR) pathway. Furthermore, additional mechanisms apart from breast related cancer antigens 1 and 2 (BRCA1/2) mutations can also result in HR pathway alterations and consequently lead to a clinical benefit from PARP inhibitors. Novel combinations of PARP inhibitors with other anticancer therapies are challenging, and better understanding of PARP biology, DNA repair mechanisms, and PARP inhibitor mechanisms of action is crucial. It seems that PARP inhibitor and biologic agent combinations appear well tolerated and clinically effective in both BRCA-mutated and wild-type cancers. They target differing aberrant and exploitable pathways in ovarian cancer, and may induce greater DNA damage and HR deficiency. The input of immunotherapy in ovarian cancer is based on the observation that immunosuppressive microenvironments can affect tumour growth, metastasis, and even treatment resistance. Several biologic agents have been studied in combination with PARP inhibitors, including inhibitors of vascular endothelial growth factor (VEGF; bevacizumab, cediranib), and PD-1 or PD-L1 (durvalumab, pembrolizumab, nivolumab), anti-CTLA4 monoclonal antibodies (tremelimumab), mTOR-(vistusertib), AKT-(capivasertib), and PI3K inhibitors (buparlisib, alpelisib), as well as MEK 1/2, and WEE1 inhibitors (selumetinib and adavosertib, respectively). Olaparib and veliparib have also been combined with chemotherapy with the rationale of disrupting base excision repair via PARP inhibition. Olaparib has been investigated with carboplatin and paclitaxel, whereas veliparib has been tested additionally in combination with temozolomide vs. pegylated liposomal doxorubicin, as well as with oral cyclophosphamide, and topoisomerase inhibitors. However, overlapping myelosuppression observed with PARP inhibitor and chemotherapy combinations requires further investigation with dose escalation studies. In this review, we discuss multiple clinical trials that are underway examining the antitumor activity of such combination strategies.

KEYWORDS:

BRCA mutations; PARP inhibitors; combination strategies; homologous recombination deficiency; ovarian cancer; synthetic lethality

PMID:
31374917
DOI:
10.3390/diagnostics9030087
Free full text

Supplemental Content

Full text links

Icon for Multidisciplinary Digital Publishing Institute (MDPI)
Loading ...
Support Center