Metabolic Reprogramming in Non-Muscle Invasive Bladder Cancer: Impact of OncoTherad® (MRB-CFI-1) Nanoimmunotherapy on Cellular Energy Metabolism

• Grant number: 24/09261-6
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: September 01, 2024
• End date: August 31, 2025
• Field of knowledge: Biological Sciences - Morphology - Anatomy
• Principal Investigator: Wagner José Fávaro
• Grantee: Manuela Gracie Nicoliello
• Host Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil

Abstract

The development and progression of cancer are characterized by a unique reprogramming of energy metabolism, essential to sustain the highly proliferative nature of neoplastic cells. The study of energy metabolism in neoplastic cells is fundamental to understanding how these cells maintain their rapid growth and proliferation, especially under adverse conditions of nutrient and oxygen availability. In the case of non-muscle invasive bladder cancer (NMIBC), this understanding is even more critical due to the profound metabolic anomalies that characterize this type of cancer. Several altered metabolic pathways play a crucial role in bladder tumorigenesis, making them attractive targets for new therapies. The treatment of bladder cancer has evolved to include immunotherapies, in addition to the standard modalities of surgery and chemotherapy. However, many high-risk NMIBC patients do not respond to Bacillus Calmette-Guérin (BCG), necessitating new therapeutic alternatives. OncoTherad® (MRB-CFI-1) emerges as a promising therapeutic alternative, demonstrating significant antitumor and immunomodulatory effects in preclinical and clinical studies, especially for intermediate- and high-risk NMIBC patients. Thus, the objectives of the present project are to characterize cellular energy metabolism and evaluate the cellular bioenergetic index (IBEC) in bladder biopsies of NMIBC patients before and after treatment with OncoTherad® (MRB-CFI-1), using the quantification of immunoreactivities associated with oxidative phosphorylation and glycolytic pathway markers, in addition to establishing clinically relevant criteria for prognosis and prediction of response to immunotherapy. This is a retrospective study involving 40 formalin-fixed, paraffin-embedded bladder tissue samples from 20 patients diagnosed with BCG-unresponsive NMIBC and subsequently treated with the nanoimmunotherapy OncoTherad® (MRB-CFI-1). Bladder biopsies from each patient will be divided into two groups (n= 20 samples per group): Group 1 [initial biopsy, before OncoTherad® (MRB-CFI-1) treatment]; and Group 2 [bladder biopsy after OncoTherad® (MRB-CFI-1) treatment]. Subsequently, these samples will undergo detailed immunohistochemical (IHC) analyses targeting PDH, CS, HADHSC, ²-F1-ATP synthase, HSP60, GLUT1, PFK, GAPDH, and LDH-A. Clinical and pathological data correlated with the IHC findings will include patient demographics, treatment details, BCG therapy outcomes, complete pathological response, recurrence-free survival, and response duration, as well as tumor size, focality, histological subtype, grade, and stage. It is expected that the characterization of metabolic markers and the evaluation of IBEC in biopsies before and after treatment with OncoTherad® (MRB-CFI-1) will provide valuable insights into the metabolic alterations associated with NMIBC and the efficacy of immunotherapy.