New Therapeutic Approaches for Non-Muscle Invasive Bladder Cancer (NMIBC): Intravesical Use of OncoTherad Biological Response Modifier and Its Association with Platelet Rich Plasma (PRP)

• Grant number: 18/10052-1
• Support type: Regular Research Grants
• Duration: October 01, 2018 - March 31, 2020
• Field of knowledge: Biological Sciences - Morphology - Anatomy
• Principal Investigator: Wagner José Fávaro
• Grantee: Wagner José Fávaro
• Home Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Assoc. researchers: Ângela Cristina Malheiros Luzo ; Athanase Billis ; Nelson Eduardo Duran Caballero

Abstract

Bladder cancer (BC) is the second most common malignant disease of the urinary tract, and one of the most costly neoplasms for the Unified Health System. The primary treatment of non-muscle invasive bladder cancer (NMIBC) is based on transurethral resection, followed by intravesical immunotherapy with Bacillus Calmette-Guérin (BCG), to decrease recurrence and prevent tumor progression. However, the use of BCG is associated with side effects of varying intensities, ranging from mild irritative symptoms to severe systemic reaction, which contributes to treatment discontinuation and has a post-treatment recurrence rate of up to 30%. In this way, the development of new therapies for the treatment of CBNMI, which are more effective and present less adverse effects than the classic therapies, are very relevant. Considering the importance of the development of drugs that can be administered intravesically and acting as modulators of the immune system, our research group developed a synthetic nanostructured compound with antitumor and immunological properties called OncoTherad (MRB-CFI-1 - Biological Response Modifier - Inorganic Phosphate Complex 1). Our group demonstrated that in the treatment of chemically induced CBNMI in mice, OncoTherad led to significant tumor regression, indicating a significant antitumor effect of this compound involving the interferon signaling pathway for Toll-like receptors (TLRs) 2 and 4-mediated. In addition, the use of phosphate moieties can exert a number of biological activities, since polyphosphates (PolyP) are secreted by activated platelets and mast cells, interfering in coagulation and innate immune response. Considering the importance of the modulation of the receptors of the immune system by these phosphate species and their relation with activated platelets, our research group investigated the importance of Platelet Rich Plasma (PRP) in the modulation of these receptors and demonstrated that PRP was able to exert antitumor effects mediated by the immune system. Thus, the main objectives of this study will be to characterize the histopathological and molecular effects of the OncoTherad nanostructured complex associated with PRP in the treatment of CBNMI chemically induced in mice, as well as to establish the possible mechanisms of action of this therapeutic association involving the TLRs 2 and 4 signaling pathways, STAT/ JAK1/JAK2 and RANK/ RANKL/ OPG cell signaling pathways, PDGF/ IGF-1/ TGF-² growth factors, and PD-1/ PD-L1 immune checkpoint pathway. (AU)