Eradication of therapy-resistant human prostate tumors using an ultrasound-guided site-specific cancer terminator virus delivery approach

Adelaide Greco, Altomare Di Benedetto, Candace M. Howard, Sarah Kelly, Rounak Nande, Yulia Dementieva, Michele Miranda, Arturo Brunetti, Marco Salvatore, Luigi Claudio, Devanand Sarkar, Paul Dent, David T. Curiel, Paul B. Fisher, Pier P. Claudio

Research output: Contribution to journalArticle

Abstract

Intratumoral injections of a replication-incompetent adenovirus (Ad) expressing melanoma differentiation-associated gene-7/interleukin-24 (Ad.mda-7), a secreted cytokine displaying cancer-selective, apoptosis-inducing properties, profoundly inhibits prostate cancer (PC) growth in immune-incompetent animals. In contrast, Ad.mda-7 is ineffective in PCs overexpressing antiapoptotic proteins such as Bcl-2 or Bcl-x L. However, intratumoral injections of a conditionally replication-competent Ad (CRCA) in which expression of the adenoviral E1A gene is driven by the cancer-specific promoter of progression-elevated gene-3 (PEG-3) and which simultaneously expresses mda-7/interleukin (IL)-24 in the E3 region of the Ad (Ad.PEG-E1A-mda-7), a cancer terminator virus (CTV), is highly active in these cells. A major challenge for gene therapy is systemic delivery of nucleic acids directly into an affected tissue. Ultrasound (US) contrast agents (microbubblesMBs) are viable candidates for gene delivery/therapy. Here, we show that MB/Ad.mda-7 complexes targeted to DU-145 cells using US dramatically reduced tumor burden in xenografted nude mice. Additionally, US-guided MB/CTV delivery completely eradicated not only targeted DU-145/Bcl-x L-therapy-resistant tumors, but also nontargeted distant tumors (established in the opposite flank), thereby implementing a cure. These findings highlight potential therapeutic applications of this novel image-guided gene therapy technology for advanced PC patients with metastatic disease.

Original languageEnglish
Pages (from-to)296-306
Number of pages11
JournalMolecular Therapy
Volume18
Issue number2
DOIs
Publication statusPublished - Feb 2010

ASJC Scopus subject areas

  • Molecular Biology
  • Molecular Medicine
  • Genetics
  • Drug Discovery
  • Pharmacology
  • Medicine(all)

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    Greco, A., Di Benedetto, A., Howard, C. M., Kelly, S., Nande, R., Dementieva, Y., Miranda, M., Brunetti, A., Salvatore, M., Claudio, L., Sarkar, D., Dent, P., Curiel, D. T., Fisher, P. B., & Claudio, P. P. (2010). Eradication of therapy-resistant human prostate tumors using an ultrasound-guided site-specific cancer terminator virus delivery approach. Molecular Therapy, 18(2), 296-306. https://doi.org/10.1038/mt.2009.252