IIBBA   05544
INSTITUTO DE INVESTIGACIONES BIOQUIMICAS DE BUENOS AIRES
Unidad Ejecutora - UE
artículos
Título:
Therapeutic improvement of a stroma-targeted CRAd by incorporating motives responsive to the melanoma microenvironment
Autor/es:
VIALE DL; CAFFERATA EG; GOULD D; ROTONDARO C; CHERNAJOVSKY Y; CURIEL DT; PODHAJCER OL; LOPEZ MV
Revista:
JOURNAL OF INVESTIGATIVE DERMATOLOGY
Editorial:
NATURE PUBLISHING GROUP
Referencias:
Lugar: Londres; Año: 2013 p. 2576 - 2584
ISSN:
0022-202X
Resumen:
We have previously designed a conditionally replicative oncolytic
adenovirus (CRAd) named Ad-F512 that can target both the stromal and the
malignant melanoma cell compartments. The replication capacity of this
CRAd is driven by a 0.5-Kb SPARC promoter fragment (named F512). To
improve CRAd's efficacy, we cloned into F512 motives responsive to
hypoxia (hypoxia-responsive element (HRE)) and inflammation (nuclear
factor kappa B) to obtain a chimeric promoter named κBF512HRE. Using
luciferase as a reporter gene, we observed 10-15-fold increased activity
under hypoxia and 10-80-fold induction upon tumor necrosis factor-α
addition. We next constructed a CRAd (Ad-κBF512HRE) where E1A activity
was under κBF512HRE regulation. Treatment of nude mice harboring
established tumors made of a mix of SB2 melanoma cells and WI-38
fibroblasts with Ad-κBF512HRE led to the complete elimination of tumors
in 100% of mice (8/8). Moreover, Ad-5/3-κBF512HRE, a viral variant
pseudotyped with a chimeric 5/3 fiber, exerted a strong lytic effect on
CAR-negative melanoma cells and was highly effective in vivo on
established tumors made of melanoma cells and WI-38 fibroblasts, leading
to the complete elimination of 4/5 tumors. These results indicate that
this improved stroma-targeted oncolytic adenovirus can override the
resistance of melanoma tumors and might become of significant importance
for melanoma therapeutics