<p>Further Understanding of High-Grade Serous Ovarian Carcinogenesis: Potential Therapeutic Targets</p>

Abstract

High-grade serous ovarian carcinoma (HGSOC) is the most common type of ovarian cancer and the most lethal gynecologic malignancy due to advanced stage at presentation. Recent years have witnessed progress in the therapy of HGSOC with the introduction of PARP (poly-adenosine diphosphate ribose polymerase) inhibitors and the anti-angiogenic monoclonal antibody bevacizumab to the backbone of chemotherapy or as maintenance therapy after chemotherapy. The improved molecular understanding of ovarian cancer pathogenesis, which has brought these therapies into the clinic, aspires to extend the boundaries of therapies through elucidation of other molecular aspects of ovarian carcinogenesis. This accumulating knowledge has started to be translated to additional targeted therapies that are in various stages of development. These include inhibitors of the function of other proteins involved in homologous recombination deficiency (HRD), such as WEE1 kinase, ATM/ATR kinases and CDK12 inhibitors. Despite disappointing results with immune checkpoint inhibitors monotherapy, harnessing the immune system in HGSOC with combination therapies that promote antigen production and immune cell activation is an avenue being explored. This paper examines arising HGSOC therapies based on molecular understanding of pathogenesis.

Increased expression of BRD4 isoforms long (BRD4-L) and short (BRD4-S) promotes chemotherapy resistance in high-grade serous ovarian carcinoma

“…In our in vitro studies, we observed that a treatment of cells with paclitaxel/adavosertib was very effective in killing Ovcar4-BRD4-L and Ovcar4-BRD4-S cells. Our findings are consistent with previous studies showing that the adavosertib effectively inhibits ovarian cancer growth as a single agent in preclinical studies [ 61 ], and improves disease outcome of platinum-resistant ovarian carcinoma patients (evaluated in phase II clinical trials) [ 62 – 64 ].…”