Emerging Therapeutic Approach for Non-Muscle Invasive Bladder Cancer through Monoamine Oxidase-A Inhibition: Assessment of the Therapeutic Potential of ImmunoClor

• Grant number: 23/15929-7
• Support Opportunities: Regular Research Grants
• Duration: March 01, 2024 - February 28, 2026
• Field of knowledge: Biological Sciences - Morphology - Anatomy
• Principal Investigator: Wagner José Fávaro
• Grantee: Wagner José Fávaro
• Host Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Associated researchers: Andrigo Barboza de Nardi ; Bianca Ribeiro de Souza ; Gabriela de Oliveira ; Marcelo Bispo de Jesus ; Nelson Eduardo Duran Caballero ; Paulo Henrique Ferreira Caria

Abstract

Immunotherapy with Bacillus Calmette-Guerin (BCG) has been the gold standard treatment for non-muscle invasive bladder cancer (NMIBC) for almost half a century. However, many high-risk disease patients experience recurrence, including those who progress and eventually do not respond to BCG. For decades, apart from radical cystectomy, few therapeutic options existed for this high-risk population. However, the advent of new immunotherapeutic agents has transformed the treatment of various tumor types, including urothelial carcinoma. These immunotherapies have shown promising results in bladder cancer treatment. In this context, our research group has developed OncoTherad® immunotherapy (MRB-CFI-1), which has shown positive results in the treatment of cancer, especially NMIBC. Based on preclinical, clinical-veterinary, and Phase 1/2 clinical studies in humans conducted in recent years, OncoTherad® immunotherapy (MRB-CFI-1) represents a new approach to combat high-grade malignant lesions in the urinary bladder before they spread to adjacent tissues and organs. However, new immunotherapies, including OncoTherad®, still need to surpass the efficacy of BCG. Due to the inherent complexity of the immune response, patient selection and the development of biomarkers to guide the identification of patients who will derive the greatest benefit from a specific immunotherapy remain critical. Most immunotherapies function by enhancing the anti-tumor responses of CD8+ T cells, which can be significantly limited by the immunosuppressive tumor microenvironment (TME). In recent years, several studies have demonstrated the upregulation of monoamine oxidase-A (MAO-A) in neoplastic tissues compared to normal tissues, and MAO-A expression has been associated with metastasis and decreased overall survival in various cancer types. The role of MAO in bladder cancer is still underexplored. Reports in the literature are scarce regarding the functions and types of MAO in normal and neoplastic bladder tissue. Furthermore, there are no studies that have investigated the association of MAO and its inhibitors in improving immunotherapy responses in bladder cancer. Thus, chemical inhibition of MAO-A may be a valuable therapeutic approach for NMIBC. Therefore, this project aims to characterize the antitumor and toxic effects of a new immunotherapeutic product, ImmunoClor, formed by combining the immunotherapeutic platform CFI-2 [Inorganic Phosphate Complex-2, similar to OncoTherad® (MRB-CFI-1)] with a MAO-A inhibitor, clorgyline. Given the importance of developing new drugs and/or therapeutic combinations for cancer in Brazil, which is known to spend a significant portion of its public health resources on the purchase of imported drugs, and particularly in the case of bladder cancer, where oncoBCG with all its known limitations is used for lack of suitable substitutes, the development of this study is essential considering the proposed objectives and expected results. The creation of technology-based products, especially applicable in the healthcare field, brings immediate returns to civil society from the investment made in university research. (AU)