Oncotarget

Research Papers:

Synergistic potentiation of the anti-metastatic effect of anti EGFR mAb by its combination with immunotherapies targeting the ganglioside NGcGM3

Addys González Palomo _, Armando López Medinilla, Valeria Segatori, María del Carmen Barroso, Rances Blanco, Mariano R. Gabri, Adriana Carr Pérez and Kalet León Monzón

PDF  |  HTML  |  Supplementary Files  |  How to cite  |  Order a Reprint

Oncotarget. 2018; 9:24069-24080. https://doi.org/10.18632/oncotarget.25290

Metrics: PDF 814 views  |   HTML 1201 views  |   ?  


Abstract

Addys González Palomo1, Armando López Medinilla1, Valeria Segatori2, María del Carmen Barroso1, Rances Blanco1, Mariano R. Gabri2, Adriana Carr Pérez1 and Kalet León Monzón1

1Center of Molecular Immunology (CIM), Atabey, Playa, Havana, Cuba

2Laboratory of Molecular Oncology, Quilmes National University, Buenos Aires, Argentina

Correspondence to:

Addys González Palomo, email: addys@cim.sld.cu

Keywords: combined therapy; metastasis-models; survival; signaling pathway; NGcGM3

Received: April 18, 2017    Accepted: March 29, 2018    Published: May 08, 2018

ABSTRACT

Several Anti-EGFR mAbs are register for the treatment of human cancer. However, their impact on patients overall survival has been limited by tumor resistance. N-Glycolyl variant of GM3 ganglioside (NGcGM3) is specifically expressed in some human tumors, and it has been associated with a poor prognosis. Several reports have documented that GM3 physically associates to EGFR inhibiting its ligand depend phosphorylation, but it also facilitates an alternative/compensatory signaling cascade mediated by Uroquinase Plasminogen Activator Receptor (uPAR) and integrin α5β1 interaction. However, the difference between NGc and N-Acetylated (NAc) variants of GM3 regarding such interactions is unknown. We hypothesized that enrichment of NGcGM3 expression in tumors relates to advantages of this ganglioside, on ensuring both EGFR and uPAR pathways optimal function. We explored the impact of combining an anti-EGFR (7A7 mAb) with anti-NGcGM3 therapies: NGcGM3/VSSP vaccine or 14F7 mAb. Both combinations synergistically increase overall survival in two models of lung metastasis: 3LL-D122 and 4T1; but combination with NGcGM3/VSSP vaccine is significantly more effective. In 3LL-D122-metastasis, of mice treated with the best combination, both EGFR and uPAR/α5β1 integrin pathways are turn off (I.e expression of uPAR/α5β1; and phosphorylation of EGFR, Stat3, Src and FAK are reduced); and tumor angiogenesis is decreased. Interestingly, combination treatment increases tumor infiltrating CD4+T, CD8+T and NK+-cells. Furthermore, a positive clinical outcome is reported for a cancer patient treated with an anti-EGFR mAb and anti-NGcGM3 therapy. Overall, our results support the combination of anti EGFR antibodies with therapies targeting NGcGM3 to increase their efficacy in future clinical trials.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
PII: 25290