TY - JOUR
T1 - Therapeutic improvement of a stroma-targeted crad by incorporating motives responsive to the melanoma microenvironment
AU - Viale, Diego L.
AU - Cafferata, Eduardo G.
AU - Gould, David
AU - Rotondaro, Cecilia
AU - Chernajovsky, Yuti
AU - Curiel, David T.
AU - Podhajcer, Osvaldo L.
AU - Lopez, M. Veronica
N1 - Funding Information:
This work was supported by grants from the National Agency for Promotion of Science and Technology (Anpcyt) Argentina, CONICET, Fundación Bunge y Born, Argentina, and 2P50CA101955 UAB/UMN Spore in Pancreatic Cancer. We are indebted to the continuous support of Amigos de la Fundación Instituto Leloir para la Investigación en Cancer (AFULIC), Argentina. We acknowledge the technical support of Florencia Straminsky.
PY - 2013/11
Y1 - 2013/11
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/84885951940
U2 - 10.1038/jid.2013.191
DO - 10.1038/jid.2013.191
M3 - Article
C2 - 23604101
AN - SCOPUS:84885951940
SN - 0022-202X
VL - 133
SP - 2576
EP - 2584
JO - Journal of Investigative Dermatology
JF - Journal of Investigative Dermatology
IS - 11
ER -