Evaluation of the protein expression of DLL-3 and ASCL-1 as a new perspective in biomarkers for the early diagnosis of small cell lung carcinomas

• Grant number: 19/12151-0
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Effective date (Start): August 01, 2019
• Effective date (End): July 31, 2022
• Field of knowledge: Health Sciences - Medicine - Pathological Anatomy and Clinical Pathology
• Principal Investigator: Vera Luiza Capelozzi
• Grantee: Tabatha Gutierrez Prieto Martins Rocha
• Host Institution: Faculdade de Medicina (FM). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 18/20403-6 - Biomolecular markers of proliferation and remodeling in acute and chronic respiratory diseases: promising therapeutic targets, AP.TEM

Abstract

Small cell lung carcinoma (NSCLC) accounts for approximately 13% of cases of lung neoplasia, is highly aggressive, frequently metastatic at the time of diagnosis, and rarely is it considered therapeutic surgical resection. Regarding the prognosis, it presents the worst estimated average survival rate in 5 years> 5%. Despite the attempt of many clinical studies in the search for new therapies, there has been no significant advance on these tumors in the last 30 years. Given this hostile scenario, it is necessary to overcome the barriers, such as the lack of markers capable of performing the early diagnosis of the disease and the limiting factor of the rapid and metastatic progression of the tumor that is associated with a lack of knowledge about the mechanisms related to the acquisition of resistance to therapies. In the search for possible candidates for biomarkers as a therapeutic and predictive target in NSCLC, this work intends to evaluate the expression of proteins that participate in important signaling pathways in tumor initiation and promotion, such as DLL-3 and ASCL-1. These proteins are highly expressed in patients' tumor tissue and play a crucial role in neoplastic evolution. DLL-3 (Delta-like protein 3) is one of the ligands of the NOTCH family, and appears to be a direct target of the ASCL-1 transcriptional factor, which is directly involved in tumor initiation of CPPC. Activation of the Notch signaling pathway in some types of tumors, such as NSCLC, may stimulate oncogenesis; however, in neuroendocrine carcinomas, it acts as a tumor suppressor. However, DLL-3 is highly expressed in most CPPCs and inhibits the Notch pathway receptor, promoting tumorigenesis. In this context, DLL-3 emerges as a possible candidate for predictive biomarker and therapeutic target. Some ongoing clinical studies have shown promising results in tests with an anti-DLL-3 drug (rovalpituzumab tesirine - Rova-T). In the same context, this study proposes to analyze the prevalence of DLL-3 in the patients involved in the study, in order to evaluate the viability of this therapy. The transcription factor ASCL-1 (Achaete-scute complex homolog-1) is highly expressed in CPPC and plays a crucial role in tumor initiation, regulating Notch signaling, and participating in the activation of oncogenes, such as MYCL1, RET, SOX2. Given the importance attributed, the ASCL-1 will be studied in this research, as a predictive biomarker in CPPC. The analysis of DLL-3 and ASCL-1 expression in tumor tissues will be performed by the immunohistochemical technique and the result of the quantification will be correlated with the clinicopathological variables of the patients. It is expected that with the results of this research we can uncover potential candidates for predictive biomarkers in CPPC, as well as corroborate with the overall survival of patients. To quantify the presence of DLL-3 and ASCL-1 in the tumor tissue of patients diagnosed with NSCL , through the immunohistochemical technique, as biomarkers in the early diagnosis of the disease; to correlate the expression of DLL-3 and ASCL-1 in the tumor tissue with the extent of neoplasia; to assess the prevalence of DLL-3 in the tumor tissue of patients diagnosed with CPPC, analyzing possible candidates for the new anti-DLL-3 therapy (Rova-T), still in clinical trials; and to correlate the expression of DLL-3 and ASCL-1 in tumor tissue with clinicopathological variables such as smoking, age, sex, relapse, treatment and staging to verify the impact on patient survival.

Scientific publications

(5)

(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)

MACHADO-RUGOLO, J.; BALDAVIRA, C. M.; PRIETO, T. G.; OLIVIERI, E. H. R.; FABRO, A. T.; RAINHO, C. A.; CASTELLI, E. C.; RIBOLLA, P. E. M.; AB'SABER, A. M.; TAKAGAKI, T.; et al. Concomitant TP53 mutation in early-stage resected EGFR-mutated non-small cell lung cancer: a narrative approach in a genetically admixed Brazilian cohort. Brazilian Journal of Medical and Biological Research, v. 56, p. 11-pg., 2023-01-01. (18/20403-6, 19/12151-0)

PRIETO, TABATHA GUTIERREZ; MACHADO-RUGOLO, JULIANA; BALDAVIRA, CAMILA MACHADO; VELOSA, ANA PAULA PEREIRA; TEODORO, WALCY ROSOLIA; AB SABE, ALEXANDRE MUXFELDT; CAPELOZZI, VERA LUIZA. The Fibrosis-Targeted Collagen/Integrins Gene Profile Predicts Risk of Metastasis in Pulmonary Neuroendocrine Neoplasms. FRONTIERS IN ONCOLOGY, v. 11, AUG 11 2021. (18/20403-6, 19/12151-0)

T.G. PRIETO; C.M. BALDAVIRA; J. MACHADO-RUGOLO; E.H.R. OLIVIERI; E.C.A. DA SILVA; V.G. SILVA; A.M. AB'SABER; T.Y. TAKAGAKI; V.L. CAPELOZZI. Clinical and morphological features of large-cell neuroendocrine carcinomas and small-cell lung carcinomas expressing the DLL3 and ASCL1 oncoproteins. Brazilian Journal of Medical and Biological Research, v. 56, 2023-12-22. (18/20403-6, 19/12151-0)

MACHADO-RUGOLO, J.; BALDAVIRA, C. M.; PRIETO, T. G.; OLIVIERI, E. H. R.; FABRO, A. T.; RAINHO, C. A.; CASTELLI, E. C.; RIBOLLA, P. E. M.; AB'SABER, A. M.; TAKAGAKI, T.; et al. Clinical outcome of Brazilian patients with non-small cell lung cancer in early stage harboring rare mutations in epidermal growth factor receptor. Brazilian Journal of Medical and Biological Research, v. 55, n. 1, p. 10-pg., 2022-01-01. (19/12151-0, 18/20403-6)

PRIETO, TABATHA GUTIERREZ; BALDAVIRA, CAMILA MACHADO; MACHADO-RUGOLO, JULIANA; FARHAT, CECILIA; RIBEIRO OLIVIERI, ELOISA HELENA; DE SA, VANESSA KAREN; ABILIO DA SILVA, EDUARDO CAETANO; BALANCIN, MARCELO LUIZ; AB SABER, ALEXANDRE MUXFELDT; TAKAGAKI, TERESA YAE; et al. Pulmonary Neuroendocrine Neoplasms Overexpressing Epithelial-Mesenchymal Transition Mechanical Barriers Genes Lack Immune-Suppressive Response and Present an Increased Risk of Metastasis. FRONTIERS IN ONCOLOGY, v. 11, AUG 30 2021. (18/20403-6, 19/12151-0)