Advances in Ovarian Cancer Treatment Beyond PARP Inhibitors

Abstract

Ovarian cancer has become the largest cause of gynaecological cancer-related mortality. It is typically diagnosed at a late stage and has no effective screening strategy. Ovarian cancer is a highly heterogeneous disease that can be subdivided into several molecular subsets. As a result of a greater understanding of molecular pathways involved in carcinogenesis and tumor growth, targeted agents have been approved or are in several stages of development. Poly(ADP-ribose) polymerase (PARP) inhibitors and the anti-vascular endothelial growth factor (VEGF)-A antibodies are two types of approved and most effective targeted drugs for ovarian cancer at present. With the success of bevacizumab, tyrosine kinase inhibitors which could target alternate angiogenic pathways are being studied. Furthermore, many treatments targeting the PI3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathways, are being developed or are already in clinical studies. MicroRNAs have also become novel biomarkers for the therapy and clinical diagnosis of ovarian cancer. This manuscript reviews the molecular, preclinical and clinical evidence supporting the targeting of growth-dependent pathways in ovarian cancer and assesses current data related to targeted treatments beyond PARP inhibitors.

Real‐world data of poly (ADP‐ribose) polymerase inhibitor response in Japanese patients with ovarian cancer

“…27 The phosphatidylinositol-3 kinase (PI3K) pathway, which plays a crucial role in chemoresistance and the preservation of genomic stability, can be a target for novel therapeutic strategies and many treatments targeting the PI3K/AKT (protein kinase B)/mTOR pathways are being developed or are already in clinical studies. 28 Besides, there have been reports that hyperthermic intraperitoneal chemotherapy (HIPEC) after cytoreductive surgery has improved the outcome of ovarian cancer, but it is not yet in the clinical practice stage. 29 In this study, we aimed to explore real-world data for olaparib and niraparib in Japan.…”

“…Although previous treatment options had been limited to chemotherapy, the advent of PARP inhibitors has offered a promising direction in the therapeutic landscape for ovarian cancer 27 . The phosphatidylinositol‐3 kinase (PI3K) pathway, which plays a crucial role in chemoresistance and the preservation of genomic stability, can be a target for novel therapeutic strategies and many treatments targeting the PI3K/AKT (protein kinase B)/mTOR pathways are being developed or are already in clinical studies 28 . Besides, there have been reports that hyperthermic intraperitoneal chemotherapy (HIPEC) after cytoreductive surgery has improved the outcome of ovarian cancer, but it is not yet in the clinical practice stage 29 …”

Prevalence and prognosis of PIK3CA mutations in Bulgarian patients with metastatic breast cancer receiving endocrine therapy in first‐line setting

“…Constantly upregulated, the PI3K pathway is crucial for genomic stability preservation, chemoresistance, and cell survival, as it is involved in numerous DNA replication and cell cycle regulation processes. By reducing the activity of the spindle assembly checkpoint protein Aurora kinase B and, as a result, increasing the frequency of lagging chromosomes during prometaphase, PI3K inhibition may result in genomic instability and mitotic disastrous consequences 14 …”

“…By reducing the activity of the spindle assembly checkpoint protein Aurora kinase B and, as a result, increasing the frequency of lagging chromosomes during prometaphase, PI3K inhibition may result in genomic instability and mitotic disastrous consequences. 14 Several genetic changes have been identified in various tumor pathways, including deletion of PTEN, amplification of AKT1 and PIK3CA, and somatic mutations in PIK3CA and AKT1. 9,15,16 The majority of point mutations in the PIK3CA gene are located in the p110 cluster, specifically around two hotspots: E542/5 in the helical domain (exon 9) and H1047R near the catalytic domain (exon 20).…”

Improving olaparib exposure to optimize adverse effects management

“…The inhibition of the PI3K may lead to genomic instability through a decrease in the spindle assembly checkpoint protein Aurora kinase B activity and, consequently, an increase in the occurrence of lagging chromosomes during prometaphase. 17 …”