Ovarian cancer (OC) is the most lethal gynecologic malignancy worldwide and it is characterized by high incidence of recurrence. Indeed, the mortality-to-incidence ratio is high as a consequence of the development of chemo-resistance and frequent metastasis. Notch signaling is thought to play a pivotal role in OC. Among the four Notch receptors, Notch3 is frequently over-expressed in OC and several studies disclosed its involvement in chemo-resistance and promotion of metastasis, thus contributing to poor overall survival of OC patients. In this scenario, the Epithelial-to-Mesenchymal Transition (EMT) process should be taken into account, as the acquisition of the mesenchymal phenotype is associated with drug resistance and metastatic capacity of malignant cells. Specifically, it has been suggested that Notch signaling regulates EMT in OC but the underlying molecular mechanism is poorly understood and needs further investigation. Since Notch3 is crucial for the pathogenesis and tumor progression of OC, Notch3 should be considered as a prognostic marker and selective targeting of Notch3 may represent a promising therapeutic approach for OC patients. We have shown that the prolyl-isomerase Pin1 positively regulates Notch3 protein in T-cell acute lymphoblastic leukemia and we hypothesized to observe the same relationship also in OC context. Therefore, the main aim of the proposed research is to broaden our knowledge of the role of Notch3 in OC metastasis and chemotherapy resistance, focusing our attention on its function and regulation by Pin1 isomerase. Evaluating how Pin1 inhibition affects Notch3-dependent OC behavior may aid in developing novel therapeutic strategies to restore chemo-sensitivity and reduce the incidence of metastasis.
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 gamma-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 [17]. 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 [18]. 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 [7, 19]. 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 [16]. 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
17. Takebe N et al, Pharmacol Ther, 2014; 18. van Es JH et al, Nature, 2005; 19. Kang H et al, Mol Carcinog, 2016.