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

53 Citations (Scopus)

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

Fingerprint

Prostate
Viruses
Adenoviridae
Genetic Therapy
Melanoma
Neoplasms
Genes
Prostatic Neoplasms
Therapeutics
Injections
Tumor Burden
Nude Mice
Nucleic Acids
Contrast Media
Apoptosis
Cytokines
Technology
interleukin-24
Growth
Proteins

ASJC Scopus subject areas

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

Cite this

Greco, A., Di Benedetto, A., Howard, C. M., Kelly, S., Nande, R., Dementieva, Y., ... 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

Eradication of therapy-resistant human prostate tumors using an ultrasound-guided site-specific cancer terminator virus delivery approach. / Greco, Adelaide; Di Benedetto, Altomare; Howard, Candace M.; Kelly, Sarah; Nande, Rounak; Dementieva, Yulia; Miranda, Michele; Brunetti, Arturo; Salvatore, Marco; Claudio, Luigi; Sarkar, Devanand; Dent, Paul; Curiel, David T.; Fisher, Paul B.; Claudio, Pier P.

In: Molecular Therapy, Vol. 18, No. 2, 02.2010, p. 296-306.

Research output: Contribution to journalArticle

Greco, A, Di Benedetto, A, Howard, CM, Kelly, S, Nande, R, Dementieva, Y, Miranda, M, Brunetti, A, Salvatore, M, Claudio, L, Sarkar, D, Dent, P, Curiel, DT, Fisher, PB & Claudio, PP 2010, 'Eradication of therapy-resistant human prostate tumors using an ultrasound-guided site-specific cancer terminator virus delivery approach', Molecular Therapy, vol. 18, no. 2, pp. 296-306. https://doi.org/10.1038/mt.2009.252
Greco, Adelaide ; Di Benedetto, Altomare ; Howard, Candace M. ; Kelly, Sarah ; Nande, Rounak ; Dementieva, Yulia ; Miranda, Michele ; Brunetti, Arturo ; Salvatore, Marco ; Claudio, Luigi ; Sarkar, Devanand ; Dent, Paul ; Curiel, David T. ; Fisher, Paul B. ; Claudio, Pier P. / Eradication of therapy-resistant human prostate tumors using an ultrasound-guided site-specific cancer terminator virus delivery approach. In: Molecular Therapy. 2010 ; Vol. 18, No. 2. pp. 296-306.
@article{52956fe7e0be4cb2968201febe16efa8,
title = "Eradication of therapy-resistant human prostate tumors using an ultrasound-guided site-specific cancer terminator virus delivery approach",
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.",
author = "Adelaide Greco and {Di Benedetto}, Altomare and Howard, {Candace M.} and Sarah Kelly and Rounak Nande and Yulia Dementieva and Michele Miranda and Arturo Brunetti and Marco Salvatore and Luigi Claudio and Devanand Sarkar and Paul Dent and Curiel, {David T.} and Fisher, {Paul B.} and Claudio, {Pier P.}",
year = "2010",
month = "2",
doi = "10.1038/mt.2009.252",
language = "English",
volume = "18",
pages = "296--306",
journal = "Molecular Therapy",
issn = "1525-0016",
publisher = "Nature Publishing Group",
number = "2",

}

TY - JOUR

T1 - Eradication of therapy-resistant human prostate tumors using an ultrasound-guided site-specific cancer terminator virus delivery approach

AU - Greco, Adelaide

AU - Di Benedetto, Altomare

AU - Howard, Candace M.

AU - Kelly, Sarah

AU - Nande, Rounak

AU - Dementieva, Yulia

AU - Miranda, Michele

AU - Brunetti, Arturo

AU - Salvatore, Marco

AU - Claudio, Luigi

AU - Sarkar, Devanand

AU - Dent, Paul

AU - Curiel, David T.

AU - Fisher, Paul B.

AU - Claudio, Pier P.

PY - 2010/2

Y1 - 2010/2

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=76349119006&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=76349119006&partnerID=8YFLogxK

U2 - 10.1038/mt.2009.252

DO - 10.1038/mt.2009.252

M3 - Article

VL - 18

SP - 296

EP - 306

JO - Molecular Therapy

JF - Molecular Therapy

SN - 1525-0016

IS - 2

ER -