Novo anticorpo com propriedades anti-tumorais para cancro da mama

Mais de 70% dos cancros da mama são positivos para o recetor de estrogénio (ER+ BC). A expressão elevada da proteína DLL1 nestes tumores está associada a maior agressividade e por conseguinte a pior prognóstico. Neste estudo, investigadores portugueses desenvolveram um anticorpo capaz de impedir a formação de metástases hepáticas em modelos animais xenotransplantados. Este estudo sugere a inibição da proteína DLL1 como uma nova abordagem no tratamento de cancros da mama positivos para o recetor de estrogénio.

Autores e afiliações:

Gabriela Silva¹, Joana Sales-Dias^1,2, Diogo Casal^3,4, Sara Alves^3,5, Giacomo Domenici^1,2, Clara Barreto^1,6, Carolina Matos¹, Ana R. Lemos^1,2, Ana T. Matias⁴, Khrystyna Kucheryava¹, Andreia Ferreira^1,4, Maria Raquel Moita^1,2, Sofia Braga^4,7_, Catarina Brito^1,2, M. Guadalupe Cabral⁴, Cristina Casalou^4,8, Duarte C. Barral⁴, Pedro M. F. Sousa^1,2, Paula A. Videira⁹, Tiago M. Bandeiras^1,2, Ana Barbas^1,10

¹ iBET, Instituto de Biologia Experimental e Tecnológica, Apartado 12, 2781-901 Oeiras, Portugal

² Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa, Av. da República, 2780-157 Oeiras, Portugal

³ Departamento de Anatomia, NOVA Medical School, Universidade NOVA de Lisboa, 1150-82 Lisboa, Portugal;

⁴ iNOVA4Health, CEDOC, NOVA Medical School, NMS, Universidade NOVA de Lisboa, 1150-82 Lisboa, Portugal;

⁵ Serviço de Anatomia Patológica, Centro Hospitalar de Lisboa Central-Hospital de São José, 1150-199 Lisboa , Portugal

⁶ Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisboa, Portugal;

⁷ Instituto CUF de Oncologia, Lisbon, Portugal.

⁸ Charles Institute of Dermatology, School of Medicine, University College Dublin, Belfield, Dublin 4, Ireland;

⁹ UCIBIO, Departamento Ciências da Vida, Faculdade de Ciências e Tecnologia, Universidade NOVA de Lisboa, 2829-516 Caparica, Portugal;

¹⁰ Bayer Portugal, 2790-143 Carnaxide, Portugal

Abstract:

Abstract: The Notch signaling ligand DLL1 has emerged as an important player and promising therapeutic target in breast cancer (BC). DLL1-induced Notch activation promotes tumor cell proliferation, survival, migration, angiogenesis and BC stem cell maintenance. In BC, DLL1 overexpression is associated with poor prognosis, particularly in estrogen receptor-positive (ER+) subtypes. Directed therapy in early and advanced BC has changed dramatically the natural course of ER+ BC, but relapse is a major clinical issue and new therapeutic strategies are needed. Here, we report the development and characterization of a novel monoclonal antibody specific to DLL1. Using phage display technology, we selected an anti-DLL1 antibody fragment that was converted into a full human IgG1 (Dl1.72). The Dl1.72 antibody exhibits DLL1 specificity and affinity in the low nanomolar range and significantly impairs DLL1-Notch signaling and expression of Notch-target genes in ER+ BC cells. Functionally, in vitro treatment with Dl1.72 reduced MCF-7 cell proliferation, migration, mammosphere formation and endothelial tube formation. In vivo, Dl1.72 significantly inhibited tumor growth, reducing both tumor cell proliferation and liver metastases in a xenograft mouse model, without apparent toxicity. Altogether, these findings suggest that anti-DLL1 Dl1.72 could be an attractive agent against ER+ BC, warranting further preclinical investigation.

Revista: MDPI Cancers 

Link: https://www.mdpi.com/2072-6694/13/16/4074