Therapeutic implications of Notch signaling in ovarian cancer

Abstract

The cancer stem cell (CSC) theory states that only some cells from a heterogeneous tumor are capable of tumorigenesis. These cells have been collectively termed ‘CSCs’ due to their stem cell-like properties of self-renewal, differentiation and tumorigenesis. It is therefore expected that therapies that target the key signalling pathways involved in CSC biology would ultimately lead to improved outcomes for the treatment of cancer patients. Notch is an evolutionary conserved signalling pathway involved in CSCs and in the development and progression of malignant tumors, like ovarian cancer. Gamma-secretase inhibitors (GSIs) are small molecules able to inhibit the Notch signalling pathway and exert antitumor effects in preclinical models. RO4929097 is one the first GSIs that entered clinical development in solid tumors based on promising early clinical efficacy data. As a result, its clinical evaluation has been conducted both in combination with chemotherapy and other targeted agents (e.g. temsirolimus) and as a single-agent in selected malignancies (e.g. ovarian cancer). The results presented herein have demonstrated that RO4929097 has a tolerable safety profile both in combination with temsirolimus in patients with solid tumors and as a single agent in women with advanced ovarian cancer. However, based on its unfavourable pharmacokinetic profile and its limited antitumor efficacy further clinical development will not be pursued. A better understanding of the biology of CSCs and their role in tumor progression, coupled with increased knowledge about the Notch signalling pathway will likely facilitate the development of other Notch-targeted agents aimed at having a clinical meaningful impact in outcomes of cancer patients.