INVESTIGADORES
PODHAJCER Osvaldo Luis
artículos
Título:
A Tumor-stroma Targeted Oncolytic Adenovirus Replicated in Human Ovary Cancer Samples and Inhibited Growth of Disseminated Solid Tumors in Mice
Autor/es:
LOPEZ MV; RIVERA AA; VIALE DL; BENEDETTI L; CUNEO N; KIMBALL KJ; WANG M; DOUGLAS J; ZHU ZB; BRAVO AI; GIDEKEL M; ALVAREZ RD; CURIEL DT; PODHAJCER OL
Revista:
MOLECULAR THERAPY (PRINT)
Editorial:
NATURE PUBLISHING GROUP
Referencias:
Lugar: Londres; Año: 2012 p. 2222 - 2233
ISSN:
1525-0016
Resumen:
Targeting the tumor stroma in addition to the malignant cell compartment
is of paramount importance to achieve complete tumor regression. In
this work, we modified a previously designed tumor stroma-targeted
conditionally replicative adenovirus (CRAd) based on the SPARC promoter
by introducing a mutated E1A unable to bind pRB and pseudotyped with a
chimeric Ad5/3 fiber (Ad F512v1), and assessed its replication/lytic
capacity in ovary cancer in vitro and in vivo. AdF512v1 was able to
replicate in fresh samples obtained from patients: (i) with primary
human ovary cancer; (ii) that underwent neoadjuvant treatment; (iii)
with metastatic disease. In addition, we show that four intraperitoneal
(i.p.) injections of 5 × 10(10) v.p. eliminated 50% of xenografted human
ovary tumors disseminated in nude mice. Moreover, AdF512v1 replication
in tumor models was enhanced 15-40-fold when the tumor contained a mix
of malignant and SPARC-expressing stromal cells (fibroblasts and
endothelial cells). Contrary to the wild-type virus, AdF512v1 was unable
to replicate in normal human ovary samples while the wild-type virus
can replicate. This study provides evidence on the lytic capacity of
this CRAd and highlights the importance of targeting the stromal tissue
in addition to the malignant cell compartment to achieve tumor
regression.