Characterization of biomarkers of ovarian cancer histological subtypes: DBMA-induced model and comparison after treatments with OncoTherad® immunotherapy and Erythropoietin

Abstract

Ovarian cancer (OC) ranks fifth among cancer deaths in women and remains the deadliest of all gynecological cancers. The OC poor outcomes highlight the need to develop new clinical approaches and especially a better understanding of this disease. Molecular analyzes have shown significant genetic heterogeneity among the OC subtypes and the importance of an assessment of underlying molecular characteristics is becoming increasingly indispensable. Specific immune activities in the tumor environment have been shown to be associated with positive outcomes in OC. OncoTherad® (MRB-CFI-1) is a nanostructured inorganic phosphate complex associated to glycosidic protein, developed by University of Campinas/ Brazil, which exhibits immunomodulatory and antitumor properties. This nano-immunotherapy leads to distinct stimulation of the innate immune system mediated by Toll-like receptors (TLRs) 2 and 4, resulting in an increased activation of the IFN signaling pathway. Erythropoietin (EPO) can exert several non-hematopoietic functions such as immunomodulation, anti-inflammatory or antioxidant and cytoprotective actions including in the ovary. The association of immunotherapy and the use of EPO is a reality in patients who are anemic due to cancer or chemotherapy treatment who may use immunotherapies. The object of this project is to evaluate the main biomarkers associated with ovarian cancer histological types to establish and characterize what histotype the DMBA-induced OC model used best represents. Through assessment of histotype-specific IHC markers, we also intend to evaluate the effects of OncoTherad® and Erythropoietin, alone or in combination, on the tumor progression to assess whether the resulting histotypes from OC induction may benefit from each treatment. We will construct the tissue microarrays (TMA) from the formalin-fixed paraffin-embedded donor blocks and evaluate the histotype-specific markers (WT1, p53, PTEN, ER, PR, PAX8, CK7, p16, HNF1B, NAPSA, ARID1A, and mismatch repair markers) and immunological markers (e.g., CD8, CD3, CD155, PD1, PDL1, and others) by immunohistochemistry. These findings will support our disease model is representative of at least one human ovarian carcinoma histotype, and functionally characterize effects of the OncoTherad® treatments. This project may bring great benefits both in providing new characterization information focusing on biomarkers of an OC model as well as in the detailed analysis of the effects of OncoTherad® nano-immunotherapy and Erythropoietin in the OC treatment taking into account the molecular histotypes characteristics. (AU)