Notch signaling is frequently activated in Ovarian Cancer (OC) and contributes to the proliferation and survival of cultured OC cells as well as to tumor formation and angiogenesis in xenograft models. Several studies demonstrate that Notch3 expression renders cancer cells more resistant to carboplatin, contributing to chemoresistance and poor overall survival of OC patients. In addition, the activation of Notch3 is also associated with potential progression of ovarian cancer, tumor invasion and metastasis, which is of high relevance in OC as most patients experience disease recurrence. In this scenario, the Epithelial-mesenchymal transition (EMT) process needs to be considered, as the acquisition of the EMT phenotype is associated with drug resistance, and Notch3 significantly interferes with the EMT regulation and the metastatic capacity of malignant cells.
This suggests that Notch3 can represent both a prognostic marker and a therapeutic target for the treatment of OC patients. However, the underlying molecular mechanisms of Notch3 activity are not yet very clear. Here, we aim to explore in details the crucial role of Notch3 in ovarian cancer metastasis and chemotherapy resistance, focusing our attention on its protein function and regulation through the involvement of the cis-trans isomerase Pin1, known to regulate the Notch3 protein via a phopshorylation-dependent mechanism. Collectively, our findings will allow us to provide novel therapeutic approaches for ovarian cancer treatment, thus improving OC patients outcome.
Overall, this study will address an urgent clinical need for OC patients, that is the identification of new valuable molecular events involved in the OC field cancerization, which would be extremely useful for identifying clinically relevant targets for cancer therapies. This proposal will provide a novel strategy for stratifying OC patients by the identification of specific biomarkers (i.e. Notch3 and Pin1) associated with drug resistance that cause the failure of treatment. Therefore, a better understanding of the Notch3-related mechanisms to the aggressive behaviour of the tumor will also provide relevant knowledge and possibly will help the development of effective strategies to stably inhibit Notch3, thus resulting in therapeutic benefit without the known toxicities associated with pan-Notch inhibition. Until recently, much work has focused on g-secretase inhibitors (GSIs) that act by preventing the cleavage of the active NICD of all isoforms of the Notch receptors, and thus inhibit their transcriptional activity. Targeting the Notch pathway either with small molecules, acting as GSIs, or large molecules, such as monoclonal antibodies (mAbs) against Notch receptors, is in clinical development [24]. Although GSI treatment has progressed into the clinic, it fails to distinguish individual Notch receptors and causes intestinal toxicity, attributed to dual inhibition of Notch1 and 2 [25]. Despite their importance, all these studies suggest that a more specific approach to Notch inhibition may prove effective. In this way, multiple studies have demonstrated that specific Notch3 inhibition sensitizes tumor cells to chemotherapy in drug-resistant OC, with an efficacy comparable to GSI [6, 26]. Thus, these findings strongly support the importance of new clinical trials aimed to evaluate more selective and less toxic Notch3 antibodies-based therapies in increasing sensitivity to platinum treatment, finally improving the outcomes of OC patients. In this proposal, the expected results will allow to increase the understanding of the specific role of the Notch3-Pin1 crosstalk in OCs, thus identifying therapeutic options based on Pin1 inhibition aimed at targeting Notch3, and finally restoring chemo-sensitivity and inhibiting metastatic spread. The Pin1 inhibitor ATRA may represent an attractive property for treating aggressive and drug-resistant OC tumors, as it exerts a potent anticancer activity against APL and triple-negative breast cancer (TNBC) by simultaneously blocking multiple Pin1-regulated cancer-driving pathways [23]. The identification of new druggable targets is one of the potential applications of this project that is oriented not only to advance the knowledge about basic mechanisms of Ovarian Cancer drug resistance but potentially to detect biological markers useful as predictive of treatment response, for single OC patient.
The novel compounds could be considered a novel strategy against ovarian cancer metastasis and thus against the acquisition of chemoresistance by tumor cells, two leading causes of ovarian cancer high mortality.
References
24. Takebe N et al, Pharmacol Ther, 2014; 25. van Es JH et al, Nature, 2005; 26. Kang H et al, Mol Carcinog, 2016.