A tumor-stroma targeted oncolytic adenovirus replicated in human ovary cancer samples and inhibited growth of disseminated solid tumors in mice

M. Veronica Lopez, Angel A. Rivera, Diego L. Viale, Lorena Benedetti, Nicasio Cuneo, Kristopher Kimball, Minghui Wang, Joanne T. Douglas, Zeng B. Zhu, Alicia I. Bravo, Manuel Gidekel, Ronald D. Alvarez, David T. Curiel, Osvaldo L. Podhajcer

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2222-2233
Number of pages12
JournalMolecular Therapy
Volume20
Issue number12
DOIs
StatePublished - Jan 1 2012

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Adenoviridae
Ovarian Neoplasms
Growth
Neoplasms
Ovary
Viruses
Neoadjuvant Therapy
Stromal Cells
Intraperitoneal Injections
Nude Mice
Endothelial Cells
Fibroblasts

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

Cite this

A tumor-stroma targeted oncolytic adenovirus replicated in human ovary cancer samples and inhibited growth of disseminated solid tumors in mice. / Lopez, M. Veronica; Rivera, Angel A.; Viale, Diego L.; Benedetti, Lorena; Cuneo, Nicasio; Kimball, Kristopher; Wang, Minghui; Douglas, Joanne T.; Zhu, Zeng B.; Bravo, Alicia I.; Gidekel, Manuel; Alvarez, Ronald D.; Curiel, David T.; Podhajcer, Osvaldo L.

In: Molecular Therapy, Vol. 20, No. 12, 01.01.2012, p. 2222-2233.

Research output: Contribution to journalArticle

Lopez, MV, Rivera, AA, Viale, DL, Benedetti, L, Cuneo, N, Kimball, K, Wang, M, Douglas, JT, Zhu, ZB, Bravo, AI, Gidekel, M, Alvarez, RD, Curiel, DT & Podhajcer, OL 2012, 'A tumor-stroma targeted oncolytic adenovirus replicated in human ovary cancer samples and inhibited growth of disseminated solid tumors in mice', Molecular Therapy, vol. 20, no. 12, pp. 2222-2233. https://doi.org/10.1038/mt.2012.147
Lopez, M. Veronica ; Rivera, Angel A. ; Viale, Diego L. ; Benedetti, Lorena ; Cuneo, Nicasio ; Kimball, Kristopher ; Wang, Minghui ; Douglas, Joanne T. ; Zhu, Zeng B. ; Bravo, Alicia I. ; Gidekel, Manuel ; Alvarez, Ronald D. ; Curiel, David T. ; Podhajcer, Osvaldo L. / A tumor-stroma targeted oncolytic adenovirus replicated in human ovary cancer samples and inhibited growth of disseminated solid tumors in mice. In: Molecular Therapy. 2012 ; Vol. 20, No. 12. pp. 2222-2233.
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