Alterations of mitochondrial morphology and dynamics in cancer: understanding of tumor biology and prospecting new therapeutic targets

• Grant number: 18/25747-5
• Support Opportunities: Regular Research Grants
• Start date: July 01, 2019
• End date: October 31, 2021
• Field of knowledge: Biological Sciences - Biochemistry - Metabolism and Bioenergetics
• Principal Investigator: Tiago Rodrigues
• Grantee: Tiago Rodrigues
• Host Institution: Centro de Ciências Naturais e Humanas (CCNH). Universidade Federal do ABC (UFABC). Ministério da Educação (Brasil). Santo André , SP, Brazil
• Associated researchers: Denise Costa Arruda ; Silvya Stuchi Maria-Engler

Abstract

Melanoma is a tumor originated in melanocytes predisposed to the accumulation of DNA damage, resulting in genetic mutations that favor its malignancy, such as the stimulation of blood vessel growth, immune response evasion, tumor invasion and metastasis. Although potentially curable sometimes, malignant melanoma is an aggressive type of cancer, with a high mortality resistance development rate to therapy. The most prevalent oncogenic mutations are already known in human melanoma, among them in B-Raf, N-Ras and c-Kit. The mutated oncoprotein BRAF (V600E) is the most prevalent genetic alteration in this type of cancer (> 50%) and results in the constant activation of BRAF conferring proliferative advantages to the melanoma cells. Among the recent therapeutic advances for the treatment of melanoma is the targeted therapy and BRAF inhibitors were developed, including the well-known drug vemurafenib. Significant tumor regression associated to improved survival rates of patients affected by melanomas with BRAF mutation in response to vemurafenib treatment, clearly demonstrates the essential role of the activation of this oncogene in the maintenance of melanoma. However, most patients treated with vemurafenib have recurrence of drug-resistant lethal melanoma. Thus, the understanding of resistance mechanisms as well as to develop tools to prevent or reverse it is of pivotal importance. Thus, in this project we will evaluate the susceptibility of BRAF and NRAS mutated human melanomas to vemurafenib, and comparatively study the alterations in mitochondrial morphology and dynamics induced by the inhibition of BRAF, in order to bring advances in the tumor biology knowledge of these types of cancer. Also, we will prospect new therapeutic targets and possible combined therapies to increase the success of the target therapy in susceptible cells and overcome the resistance of non-responsive melanoma cells to vemurafenib. (AU)

Scientific publications

(10)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

COLTURATO-KIDO, CARINA; LOPES, RAYSSA M.; MEDEIROS, HYLLANA C. D.; COSTA, CLAUDIA A.; PRADO-SOUZA, LAURA E. L.; FERRAZ, LETICIA S.; RODRIGUES, TIAGO. nhibition of Autophagy Enhances the Antitumor Effect of Thioridazine in Acute Lymphoblastic Leukemia Cell. LIFE-BASEL, v. 11, n. 4, APR 2021. (16/07367-5, 18/25747-5)

COSTA, CLAUDIA A.; LOPES, RAYSSA M.; FERRAZ, LETICIA S.; ESTEVES, GABRIELA N. N.; DI IORIO, JULIANA F.; SOUZA, ALINE A.; DE OLIVEIRA, ISADORA M.; MANARIN, FLAVIA; JUDICE, WAGNER A. S.; STEFANI, HELIO A.; et al. Cytotoxicity of 4-substituted quinoline derivatives: Anticancer and antileishmanial potential. Bioorganic & Medicinal Chemistry, v. 28, n. 11, JUN 1 2020. (16/04289-3, 18/25747-5, 16/25112-4, 17/24821-4, 14/02205-1)

RODRIGUES, TIAGO; FERRAZ, LETICIA SILVA. Protocol Cytosolic Ca2+ measurements by ratiometric fluorescence microscopy in melanoma cells. STAR PROTOCOLS, v. 2, n. 1, p. 12-pg., 2021-03-19. (18/25747-5)

ESTEVES, GABRIELA NOHEMI NUNEZ; FERRAZ, LETICIA SILVA; ALVAREZ, MARCELA MACIEL PALACIO; DA COSTA, CLAUDIA ALVES; LOPES, RAYSSA DE MELLO; TERSARIOL, IVARNE LUIS DOS SANTOS; RODRIGUES, TIAGO. BRAF and NRAS mutated melanoma: Different Ca2+ responses, Na+/Ca2+ exchanger expression, and sensitivity to inhibitors. Cell Calcium, v. 90, SEP 2020. (18/25747-5, 16/07367-5, 15/03964-6)

COLTURATO-KIDO, CARINA; LOPES, RAYSSA M.; MEDEIROS, HYLLANA C. D.; COSTA, CLAUDIA A.; PRADO-SOUZA, LAURA E. L.; FERRAZ, LETICIA S.; RODRIGUES, TIAGO. Inhibition of Autophagy Enhances the Antitumor Effect of Thioridazine in Acute Lymphoblastic Leukemia Cells. LIFE-BASEL, v. 11, n. 4, p. 14-pg., 2021-04-01. (16/07367-5, 18/25747-5)

RODRIGUES, TIAGO; PICCIRILLO, SILVIA; MAGI, SIMONA; PREZIUSO, ALESSANDRA; RAMOS, VYCTORIA DOS SANTOS; SERFILIPPI, TIZIANO; ORCIANI, MONIA; ALVAREZ, MARCELA MACIEL PALACIO; TERSARIOL, IVARNE LUIS DOS SANTOS; AMOROSO, SALVATORE; et al. Control of Ca2+ and metabolic homeostasis by the Na+/Ca2+ exchangers (NCXs) in health and disease. Biochemical Pharmacology, v. 203, p. 14-pg., 2022-07-12. (18/25747-5)

JUDICE, WAGNER A. S.; FERRAZ, LETICIA SILVA; LOPES, RAYSSA DE MELLO; VIANNA, LUAN DOS SANTOS; SIQUEIRA, FABIO DA SILVA; DI IORIO, JULIANA F.; DALZOTO, LAURA DE AZEVEDO MAFFEIS; TRUJILHO, MARIANA NASCIMENTO ROMERO; SANTOS, TAIZ DOS REIS; MACHADO, MAURICIO F. M.; et al. Cysteine proteases as potential targets for anti-trypanosomatid drug discovery. Bioorganic & Medicinal Chemistry, v. 46, SEP 15 2021. (18/25747-5, 16/25112-4, 19/05936-0)

FERRAZ, LETICIA SILVA; DA COSTA, RENATA TORRES; DA COSTA, CLAUDIA ALVES; JOAO RIBEIRO, CESAR AUGUSTO; ARRUDA, DENISE COSTA; MARIA-ENGLER, SILVYA STUCHI; RODRIGUES, TIAGO. Targeting mitochondria in melanoma: Interplay between MAPK signaling pathway and mitochondrial dynamics. Biochemical Pharmacology, v. 178, AUG 2020. (18/11972-7, 18/25747-5, 17/04926-6, 15/25541-0)

RODRIGUES, TIAGO; FERRAZ, LETICIA SILVA. Therapeutic potential of targeting mitochondrial dynamics in cancer. Biochemical Pharmacology, v. 182, DEC 2020. (18/25747-5)

MORAES, VIVIAN W. R.; SANTOS, VIVIAN M.; SUAREZ, ELOAH R.; FERRAZ, LETICIA S.; LOPES, RAYSSA DE MELLO; MOGNOL, GIULIANA P.; CAMPEIRO, JOANA D.; MACHADO-NETO, JOAO A.; NASCIMENTO, FABIO D.; HAYASHI, MIRIAN A. F.; et al. Targeting Ca2+ and Mitochondrial Homeostasis by Antipsychotic Thioridazine in Leukemia Cells. LIFE-BASEL, v. 12, n. 10, p. 20-pg., 2022-10-01. (20/01107-7, 16/07367-5, 18/25747-5, 06/00995-9, 17/02413-1, 21/11606-3)