Epithelial Ovarian cancer (EOC) is a rare but highly letal disease, as acquired resistance to standard Platinum (PT)-based therapies occurs frequently and predicts poor prognosis. Recurrent resistant EOCs almost grow as metastatic disease commonly involving peritoneum, omentum and secondary organs located in the abdominal cavity. In this scenario, elucidating which pathways are involved in EOC aggressive behaviour becomes a paramount issue in order to improve PT-response, which is still a great challenge. Notch signaling is frequently activated in OC and contributes to tumor formation and angiogenesis in xenograft models. In particular, Notch3 activation is frequently associated with OC progression, tumor invasion and metastasis, thus suggesting its potential involvement in PT-resistance. Both chemoresistance and tumor dissemination have been linked to the Epithelial-mesenchymal transition (EMT) process as well as to the cancer stem cell (CSC)-like phenotype acquisition. It has been demonstrated that Notch3 significantly interferes both with the EMT regulation and the metastatic capacity of malignant cells in OC. This suggests that Notch3 may represent both a prognostic marker and a therapeutic target that can be exploited to improve PT
efficacy in EOC 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 EOC metastasis and chemotherapy resistance, focusing our attention on its function and regulation by Pin1 isomerase. Evaluating how Pin1 inhibition affects Notch3-dependent EOC 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 EOC patients, that is the identification of new valuable molecular events involved in the EOC field cancerization, which would be extremely useful for identifying clinically relevant targets for cancer therapies. This proposal will provide a novel strategy for stratifying EOC 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 ¿-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 [27]. 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 [28]. 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, 29]. 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 [21]. 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 OC metastasis and thus against the acquisition of chemoresistance by tumor cells, two leading causes of OC high mortality.
References
1. Siegel RL et al, CA Cancer J Clin 2016; ¿2. Matulonis UA et al, Nat Rev Dis Primers 2016; 3. Armstrong DK et al, The New England Journal of Medicine 2006; 4. Aster JC et al, Annual Rev of Pathology 2017; 5. Bell D et al, Nature 2011; 6. Ceccarelli S et al, Stem Cells Int 2019; 7. McAuliffe SM et al, Proc Natl Acad Sci U S A 2012; 8. Pazos MC et al, Molecular and Cellular Endocrinology 2017; 9. Culig Z, Bioc et Bioph Acta Mol Cell Res 2019; 10. Park JT et al, Cancer Res 2006; 11. Park JT et al, Am J Pathol 2010; 12. Li H et al, International Journal of Cancer 2019; 13. Xu Y et al, Cancer Medicine 2019;14. Espinoza I and Miele L, Oncotargets 2013; 15. Zhou L et al, PlosOne 2013; 16. Franciosa G et al, Oncogene 2016; 17.Domcke S et al, Nat Commun 2013; 18.Rustighi A et al, EMBO Mol Med 2014; 19.Sonego M et al, Sci Rep. 2017; 20.Sonego M et al, Sci Adv 2019; 21.Wei S et al, Nat Med 2015; 22.Jung JG et al, PLoS Gen 2014; 23.Bernassola F et al, Cancer Cell 2008; 24.Munt T et al, Open Biol 2015; 25.Sudol M et al, IUBMB Life 2005; 26.Chen Z et al, Mol Cell 2017; 27.Takebe N et al, Pharmacol Ther, 2014; 28.van Es JH et al, Nature, 2005; 29.Kang H et al, Mol Carcinog, 2016.