Ovarian cancer (OC) is the most lethal gynecological malignancy worldwide. Standard therapeutic approaches for OC involve surgery, chemotherapy and radiotherapy but, despite the initial efficacy, 5-year survival rates remain unfavorable. Around 70% of OC patients develops disease recurrence and needs subsequent treatment lines, which are rarely curative but rather palliative. OC relapsing is mainly due to the expansion of cancer stem cells (CSCs), having the ability of self-renew and resistance to conventional therapies. Non-coding RNAs (ncRNAs) and epigenetic drivers have been shown to be essential in the OC biology and represent potential targets for anticancer treatments since they can be finely tuned and reprogrammed. In the era of "network medicine", we will integrate the high-throughput gene expression and epigenetic profile data, freely available in different tumor-related platforms (TCGA and GEO), with the OC histopathological and molecular features. The nodes and edges of this network-based approach will be crucial for the elucidation of the complex interactions between the OC-associated ncRNAs and epigenetic modifications, and for the identification of novel therapeutic targets and biomarkers. So, we will validate the expression of the identified genes and methylation/acetylation profiles in OC samples in order to define their diagnostic/prognostic value. We will also evaluate the antitumoral activity of selected agents (epi-drugs or ncRNAs) in OC cellular models, as single agents or in combination with radiation therapy, focusing on their effects on CSC-related pathways. Our understanding of the molecular networks that govern OC development and drug resistance will provide new insights for personalized combinatorial therapies, which might be translated into more efficient and less toxic treatments for OC patients.
Ovarian cancer (OC) represents the fifth most frequent cause of cancer-related deaths in women. It has by far the worst prognosis of all gynecological cancers and is responsible for half the deaths caused by female genital tract malignancy, with about 150,000 deaths a year. Despite worldwide research into this field and the overall cure rate has increased, the long-term prognosis for patients with metastatic and recurrent tumors remains dismal with few new options for treatment. Conventional therapies, including debulking surgery, cytotoxics and radiotherapy, still represent the standard treatments for OC tumors, but a subgroup of patients undergoes a rapid disease progression or eventually relapses shortly after treatment because of the appearance of resistant cancer cells. Chemo/radiotherapy is also associated with significant acute and chronic toxicity (i.e. myelosuppression, nephrotoxicity, infertility, cardiomyopathy) and with an increased risk of life-threatening late events such as secondary malignancies. Furthermore, due to the absence of evident symptoms at early stage, OC patients are often diagnosed in advanced stage of the disease, when metastatic spread is high. At the present time, there is still lack of ideal screening tests and programs for the early detection of OC tumors. Consequently, novel biomarkers should be thoroughly investigated for an early and accurate diagnosis and to aid in the selective targeted therapies to improve the disease outcome. Aberrant expression of epigenetic enzymes, specifically responsible of DNA methylation and histone acetylation/methylation at definite aminoacidic residues, and ncRNAs, which regulate gene expression at post-transcriptional levels, have been shown to contribute to the transformation of a "healthy" cell into a tumor cell. Indeed, the resultant epigenome imbalance, due to the inactivation of tumor suppressor genes and the activation of oncogenes, plays a central role in the development and progression of many tumors, including OC.
We aim to offer a novel approach in OC research to unravel the molecular networks that harbor gene drivers of this fatal disease. Our integrated study of genome-wide epigenetic and gene expression data in OC tumors from TCGA and GEO databases will lead us to identify epigenetic marks, such as methylation/acetylation and ncRNAs, that are aberrantly found in OC biopsies comparing with normal ovarian tissues. We will correlate these in silico analyses with biological processes and functions in OC and with the tumor histological type, including OC grading, in order to identify how tumor-related genes and ncRNAs interact each other to create a molecular network of tumorigenesis. In this network, we will be able to select several crucial genes and evaluate their potential use as diagnostic/prognostic biomarkers as well as targets for personalized therapies. In this context, the quantification of OC stage/grade-related-circulating-miRNAs in patient¿s blood will be fundamental for choosing reliable biomarkers for an early diagnosis, a more appropriate stratification into risk classes and response to therapies. Furthermore, the identification of specific epigenetic mechanisms and/or altered expression of epigenetic enzymes will give us indications for epi-drug therapies. Indeed, current preclinical studies and "phase 1/2" clinical trials on different malignancies are focused on several epigenetic components, aiming at restoring the appropriate transcriptome and methylome patterns. Based on this evidence, we believe that the evaluation of the activity of novel epigenetic drugs (such as OTX015) and selected ncRNAs in OC cellular lines, both as single agents or in combination between them or with radiotherapy, might provide an additional therapeutic approach for OC patients and a deeper insight into the molecular mechanisms underlying tumorigenesis of this aggressive female tumor. As mentioned above, the overall survival rate of OC women treated with conventional therapies is very poor and the need for effective clinical protocols based on combinatorial therapies is mandatory. Of particular importance will be also the evaluation of the effects of epi-drugs or specific ncRNAs on the formation of tumor spheres, associated with cancer stem cell (CSC) proliferation and maintenance, since the reduction in CSC metastatic potential should be a promising approach to improve the efficacy of cancer treatment and, in turn, the chances of patient survival. Finally, the assessment of the combinatorial therapies in OC in vitro models will give a rationale to translate experiments in preclinical mouse models in the attempt of designing more effective and less toxic therapeutic protocols for the management of OC women. Ultimately this project might allow an improvement of the therapeutic index in terms of reducing the side effects and increasing the quality of life, especially in those patients with high-risk disease.