Study of biomarkers of cetuximab response and perspective of application of anti-EGFR combi-molecules in solid tumors

• Grant number: 17/22305-9
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: November 01, 2018
• End date: February 07, 2021
• Field of knowledge: Biological Sciences - Genetics - Human and Medical Genetics
• Principal Investigator: Rui Manuel Vieira Reis
• Grantee: Izabela Natalia Faria Gomes
• Host Institution: Hospital do Câncer de Barretos. Fundação Pio XII (FP). Barretos , SP, Brazil

Abstract

The Epidermal Growth Factor Receptor (EGFR) is an important protein which activation leads to the signaling of intracellular pathways that act directly on cell proliferation, migration and survival. Cetuximab (CTX), is an anti-EGFR monoclonal antibody that has been approved for the treatment of Head and Neck Squamous Cell Carcinoma (HNSCC) patients and metastatic Colorectal Cancer (mCRC). The response of mCRC patients to CTX is associated with wild type KRAS mutation. However, for HNSCC patients until now any biomarker predictive of CTX response is available, making it impossible to select patients who could benefit from this agent. Preliminary results from our group, using established isogenic cetuximab-resistant HNSCC cell lines, revealed that the resistant phenotype could be due to overexpression of genes involved in EGFR, MAPK and mTOR pathaways, and repression of the genes involved in WNT pathway. On the other hand, considering the acquired resistance to molecular therapies and intracellular crosstalk, the design of "combi-molecules" is an innovative and promising approach. This new concept was developed by Prof. Jean-Claude (MCGill University), co-supervisor of the present study, and on the context of the bilateral project supported by CAPES/DFATD Program. "Combi-molecules" are designed to have two or three targets, such as inhibition of DNA repair and at the same time blockage of EGFR-mediated signaling. Therefore, this project aims to: a) find biomarkers predictive of CTX response in HNSCC resistant cell lines; and b) evaluate the antineoplastic activity of "combi-molecules" in solid tumors. In order to achieve these objectives we will perform the integrated molecular profile involving the study of chromosomal alterations, RNA and microRNA expression profile, methylation and the presence of mutations between sensitive and resistant cell lines. Functional assays will be used also to validate the biomarkers and characterize the antineoplastic activity of the "combi-molecules" through in vitro and in vivo studies. In this work we intend to identify and validate new predictive biomarkers of CTX response that can be used in clinical practice for patient selection, as well to evaluate the effect of new anticancer drugs, based on the "combi-molecules" concept, for the treatment of head and neck and colorectal tumors. (AU)

Scientific publications

(6)

(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)

LENGERT, ANDRE VAN HELVOORT; BRAGA PEREIRA, LETICIA DO NASCIMENTO; MARTINS CABRAL, EDUARDO RAMOS; FARIA GOMES, IZABELA NATALIA; DE JESUS, LAIS MACHADO; SANTIAGO GONCALVES, MARIA FERNANDA; DA ROCHA, ALINE OLIVEIRA; TASSINARI, TIAGO ALEXANDRE; DA SILVA, LUCIANE SUSSUCHI; LAUS, ANA CAROLINA; et al. Potential New Therapeutic Approaches for Cisplatin-Resistant Testicular Germ Cell Tumors. FRONTIERS IN BIOSCIENCE-LANDMARK, v. 27, n. 8, p. 13-pg., 2022-08-15. (17/22305-9)

DE MENEZES, WEDER PEREIRA; OLIVEIRA SILVA, VIVIANE ALINE; FARIA GOMES, IZABELA NATALIA; ROSA, MARCELA NUNES; CORCOLL SPINA, MARIA LUISA; CARLONI, ADRIANA CRUVINEL; VIEIRA ALVES, ANA LAURA; MELENDEZ, MATIAS; ALMEIDA, GISELE CARAVINA; DA SILVA, LUCIANE SUSSUCHI; et al. Loss of 5 '-Methylthioadenosine Phosphorylase (MTAP) is Frequent in High-Grade Gliomas; Nevertheless, it is Not Associated with Higher Tumor Aggressiveness. CELLS, v. 9, n. 2, p. 24-pg., 2020-02-01. (16/18907-0, 16/06833-2, 17/22305-9)

DE MENEZES, WEDER PEREIRA; OLIVEIRA SILVA, VIVIANE ALINE; FARIA GOMES, IZABELA NATALIA; ROSA, MARCELA NUNES; CORCOLL SPINA, MARIA LUISA; CARLONI, ADRIANA CRUVINEL; VIEIRA ALVES, ANA LAURA; MELENDEZ, MATIAS; ALMEIDA, GISELE CARAVINA; DA SILVA, LUCIANE SUSSUCHI; et al. Loss of 5 `-Methylthioadenosine Phosphorylase (MTAP) is Frequent in High-Grade Gliomas; Nevertheless, it is Not Associated with Higher Tumor Aggressiveness. CELLS, v. 9, n. 2, FEB 2020. (16/18907-0, 17/22305-9, 16/06833-2)

ALVES, ANA LAURA V.; GOMES, IZABELA N. F.; CARLONI, ADRIANA C.; ROSA, MARCELA N.; DA SILVA, LUCIANE S.; EVANGELISTA, ADRIANE F.; REIS, RUI MANUEL; SILVA, VIVIANE ALINE O.. Role of glioblastoma stem cells in cancer therapeutic resistance: a perspective on antineoplastic agents from natural sources and chemical derivatives. STEM CELL RESEARCH & THERAPY, v. 12, n. 1, MAR 24 2021. (17/22305-9, 19/05142-4)

RIBEIRO, DIEGO LUIS; TUTTIS, KATIUSKA; BASTOS DE OLIVEIRA, LARISSA CRISTINA; SERPELONI, JULIANA MARA; FARIA GOMES, IZABELA NATALIA; LENGERT, ANDRE VAN HELVOORT; DA ROCHA, CLAUDIA QUINTINO; REIS, RUI MANUEL; DE SYLLOS COLUS, ILCE MARA; GREGGI ANTUNES, LUSANIA MARIA. The Antitumoral/Antimetastatic Action of the Flavonoid Brachydin A in Metastatic Prostate Tumor Spheroids In Vitro Is Mediated by (Parthanatos) PARP-Related Cell Death. PHARMACEUTICS, v. 14, n. 5, p. 20-pg., 2022-05-01. (17/22305-9)

JOSE DA SILVA-OLIVEIRA, RENATO; FARIA GOMES, IZABELA NATALIA; DA SILVA, LUCIANE SUSSUCHI; LENGERT, ANDRE VAN HELVOORT; LAUS, ANA CAROLINA; MELENDEZ, MATIAS ELISEO; MUNARI, CARLA CAROLINA; CURY, FERNANDA DE PAULA; LONGATO, GIOVANNA BARBARINI; REIS, RUI MANUEL. Efficacy of Combined Use of Everolimus and Second-Generation Pan-EGRF Inhibitors in KRAS Mutant Non-Small Cell Lung Cancer Cell Lines. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v. 23, n. 14, p. 16-pg., 2022-07-01. (17/22305-9)