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ADVERSE EVENTS OF TREATMENT IN ADVANCED NON-SMALL CELL LUNG CANCER: CONTRIBUTION OF CLINICAL, GENETIC AND EPIGENETIC FACTORS

Grant number: 23/06280-7
Support Opportunities:Regular Research Grants
Duration: March 01, 2024 - February 28, 2026
Field of knowledge:Health Sciences - Pharmacy
Principal Investigator:Patricia Moriel
Grantee:Patricia Moriel
Host Institution: Faculdade de Ciências Farmacêuticas (FCF). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
Associated researchers:Eder de Carvalho Pincinato ; José Luiz da Costa ; KATHLEEN SAAVEDRA ; Luis Salazar Navarrete ; Marília Berlofa Visacri ; Maurício Wesley Perroud Júnior ; Paulo Caleb Júnior de Lima Santos

Abstract

Lung carcinoma is the main cause of cancer-related morbidity and mortality in the world, with more than 2.2 million of new cases and 1.8 of deaths estimated to 2020. The most common type of lung cancer is the non-small cell lung carcinoma (NSCLC). The treatment strategy in advanced NSCLC has evolved from empirical chemotherapy to a personalized approach based on better histological and molecular characterization of NSCLC primary tumors. Despite the great advances made in targeted therapies and immunotherapy, platino-based chemotherapy treatments continue to be used. In this research we will focus on treatments based on Platinum-based doublets combined paclitaxel and to gefitinib (EGFR-mutated NSCLC treatment). Platinum derivatives use is limited mainly due to important toxicities, such as myelotoxicity, nephro, gastrointestinal and liver toxicities, and considerable inter-individual differences have been reported regarding to theses toxicities. In the same way, the use of gefitinib, the first molecular targeted agent for NSCLC, by targeting EGFR inhibiting tyrosine kinase, report serious and frequent side effects such as diarrhea and skin rash, have been reported in more than half of the. The literature suggests that there are clinical, genetic and epigenetic factors that could be involved in the development of these adverse effects, of which the most frequent are myelotoxicity in the case of carboplatin +paclitaxel treatments and skin rash in the case of treated patients with gefitinib. Based on this background, the following the generals' objectives are proposed: 1) To identify clinical, genetic and epigenetic factors related to carboplatin/paclitaxel or gefitinib induced toxicities in NSCLC; 2) To describe the contribution of deregulated miRNAs in plasma from NSCLC patients on carboplatin/paclitaxel-induced myelotoxicity and gefitinib-induced skin rash. Methodology: O.1) The study design is an observational and prospective study with a consecutive and non-probabilistic sampling strategy. Patients will be grouped into A) carboplatin + paclitaxel group (without EGRF mutation): from each patient will be obtained blood samples prior and 20 days after to carboplatin/paclitaxel administration, and B) gefitinib group (with EGRF mutation, who start or are already part of the treatment protocol with Gefitinib): from each patient will be obtained blood samples 30 days after gefitinib administration. From all patients of both groups will be obtained clinical and demographic data. All toxicities will be graded according to National Cancer Institute Common Toxicity Criteria for Adverse Events version 5 Evaluation of genetic polymorphisms by PCR through TaqMan SNP Genotyping Assays will be performed. Evaluation of miRNAs expression will be performed by sequencing to determine differentially expressed miRNAs and after validation by RTPCR. O.2) Target prediction will be performed using TargetScan to differentially express miRNAs detected in the in vivo study, combined with Ingenuity Pathway Analysis bioinformatic analysis to evaluate the implications of the altered miRNA expression on mRNA expression and to select targets genes potentially related to toxicities. In vitro validation of miRNA-mRNA interaction will be evaluated by luciferase assay. In vitro functional assay will be performed to validate the miRNAs contribution on the process of myelo and skin toxicity. The expression of miRNAs will be modulated by overexpression using mimics and by repression using, we will work with the two cell lines of myeloid lineage and two of epidermal lineage. The functional assays to be evaluated will depend on the target related to the selected miRNAs. In addition, the gene expression (by real-time PCR) and protein expression (by western blot) of the target genes related to the validated miRNAs will be evaluated. (AU)

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