Ultrasound-guided gene delivery in pancreatic cancer

Summary

Principal Investigator: Pier Paolo Claudio
Abstract: DESCRIPTION (provided by applicant): At present, no effective therapy is available for metastatic pancreatic cancer. This proposal seeks to overcome this impasse by employing a novel approach employing a cancer-specific conditionally replication competent adenovirus that expresses a therapeutic cytokine, IFN-? or mda-7/IL-24 (a cancer terminator virus (CTV)), in combination with an ultrasound (US) contrast agent and US waves. These studies are based on the observations that IFN-? and mda-7/IL-24 displays selective anti-pancreatic cancer activity, potent 'bystander'anti-tumor activity, anti-angiogenic activity. Based on profound multifunctional, selective anti-cancer activities of mda-7/IL-24, this gene has been evaluated in a Phase I clinical trial in patients with advanced cancers, not including pancreatic cancer, by repeat intratumoral injections with a non-replicating adenovirus (Ad) expressing mda-7/IL-24 (Ad.mda-7;INGN 241). This therapeutic approach was safe and resulted in significant clinical activity. Restrictions of Ad-based therapies include rapid degradation and clearance by the immune system, thus limiting systemic applications. By using US contrast agents (microbubbles) we will achieve both specificity of action as well as protection of the viral vectors from inactivation. Additionally, the gas filled microspheres effectively lower the energy threshold for cavitation allowing diagnostic transducers operating within the energy levels mandated by the FDA to be used for drug/gene delivery. In the sonification zone the microbubbles undergo cavitation, destroying the bubbles and releasing their contents, creating small shockwaves that increase cell permeability. This has been shown to increase transcapillary passage of macromolecules or nanospheres co-delivered by the microbubbles in experimental animals. In principle, the present approach should allow efficient CTV delivery and may evoke a cure in both primary and distant mestastatic pancreatic cancer, which will be tested in immune incompetent animal models. Successful accomplishment of these studies will pave the way for future clinical trials. PUBLIC HEALTH RELEVANCE: The present study seeks to develop an effective therapy for pancreatic cancer that employs cancer-specific apoptosis-inducing cytokines, IFN-? or mda-7/IL-24, delivered by a conditionally replication competent adenovirus, a cancer terminator virus (CTV), in combination with ultrasound contrast agents and ultrasound waves. This novel approach will permit efficient systemic delivery of the CTV to tumors, offering the potential to develop a 'cure'for both localized and metastatic pancreatic cancer. Successful achievement of the objectives of the present proposal will provide for rapid translation into the clinic as a new and potentially effective therapy for metastatic pancreatic cancer.
Funding Period: ----------------2009 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. pmc Targeting a newly established spontaneous feline fibrosarcoma cell line by gene transfer
    Rounak Nande
    Department of Biochemistry and Microbiology, Joan C Edwards School of Medicine, Marshall University, Huntington, West Virginia, United States of America
    PLoS ONE 7:e37743. 2012
  2. pmc Omega-3 eicosapentaenoic acid decreases CD133 colon cancer stem-like cell marker expression while increasing sensitivity to chemotherapy
    Flavia de Carlo
    Department of Biochemistry and Microbiology, Joan Edwards School of Medicine, Marshall University, Huntington, West Virginia, United States of America
    PLoS ONE 8:e69760. 2013
  3. pmc Benzyl isothiocyanate inhibits HNSCC cell migration and invasion, and sensitizes HNSCC cells to cisplatin
    M Allison Wolf
    a McKown Translational Genomic Research Institute and Department of Biochemistry and Microbiology, Joan C Edwards School of Medicine, Marshall University, Huntington, West Virginia, USA
    Nutr Cancer 66:285-94. 2014
  4. pmc Eradication of therapy-resistant human prostate tumors using an ultrasound-guided site-specific cancer terminator virus delivery approach
    Adelaide Greco
    Department of Biochemistry and Microbiology, Joan C Edwards School of Medicine, Marshall University, Huntington, West Virginia 25755, USA
    Mol Ther 18:295-306. 2010
  5. pmc Rapid selection and proliferation of CD133+ cells from cancer cell lines: chemotherapeutic implications
    Sarah E Kelly
    Department of Biochemistry and Microbiology, Joan C Edwards School of Medicine, Marshall University, Huntington, West Virginia, United States of America
    PLoS ONE 5:e10035. 2010
  6. pmc A novel phantom model for mouse tumor dose assessment under MV beams
    Michael S Gossman
    Tri State Regional Cancer Center, Radiation Oncology Department, 706 23rd Street, Ashland, KY 41101, USA
    Health Phys 101:746-53. 2011
  7. pmc Cadmium induces p53-dependent apoptosis in human prostate epithelial cells
    Pierpaolo Aimola
    Department of Biochemistry and Microbiology, Joan C Edwards School of Medicine, Marshall University, Huntington, West Virginia, United States of America
    PLoS ONE 7:e33647. 2012

Scientific Experts

  • Michael Gossman
  • Pier Paolo Claudio
  • Altomare Di Benedetto
  • Flavia de Carlo
  • Pierpaolo Aimola
  • Rounak Nande
  • Adelaide Greco
  • M Allison Wolf
  • Luigi Claudio
  • Sarah E Kelly
  • Candace M Howard
  • Theodore R Witte
  • W Elaine Hardman
  • Jagan Valluri
  • Miranda Carper
  • Charlene D Claudio
  • Adrie van Bokhoven
  • Gary C Duncan
  • Jim Denvir
  • Michael P Waalkes
  • Anna Rita Volpe
  • Marco Carmignani
  • Erik J Tokar
  • Paul Dent
  • David T Curiel
  • Vincent E Sollars
  • Jagan V Valluri
  • Marco Salvatore
  • Sarah Kelly
  • Donald A Primerano
  • Arturo Brunetti
  • Devanand Sarkar
  • Michele Miranda
  • Yulia Dementieva
  • Paul B Fisher

Detail Information

Publications8

  1. pmc Targeting a newly established spontaneous feline fibrosarcoma cell line by gene transfer
    Rounak Nande
    Department of Biochemistry and Microbiology, Joan C Edwards School of Medicine, Marshall University, Huntington, West Virginia, United States of America
    PLoS ONE 7:e37743. 2012
    ..More gene transfer studies should be conducted in order to understand if these viral vectors could be applicable regardless the origin (spontaneous vs. vaccine induced) of feline fibrosarcomas...
  2. pmc Omega-3 eicosapentaenoic acid decreases CD133 colon cancer stem-like cell marker expression while increasing sensitivity to chemotherapy
    Flavia de Carlo
    Department of Biochemistry and Microbiology, Joan Edwards School of Medicine, Marshall University, Huntington, West Virginia, United States of America
    PLoS ONE 8:e69760. 2013
    ....
  3. pmc Benzyl isothiocyanate inhibits HNSCC cell migration and invasion, and sensitizes HNSCC cells to cisplatin
    M Allison Wolf
    a McKown Translational Genomic Research Institute and Department of Biochemistry and Microbiology, Joan C Edwards School of Medicine, Marshall University, Huntington, West Virginia, USA
    Nutr Cancer 66:285-94. 2014
    ..Consequently, the results indicate that further investigation, including in vivo studies, are warranted...
  4. pmc Eradication of therapy-resistant human prostate tumors using an ultrasound-guided site-specific cancer terminator virus delivery approach
    Adelaide Greco
    Department of Biochemistry and Microbiology, Joan C Edwards School of Medicine, Marshall University, Huntington, West Virginia 25755, USA
    Mol Ther 18:295-306. 2010
    ..These findings highlight potential therapeutic applications of this novel image-guided gene therapy technology for advanced PC patients with metastatic disease...
  5. pmc Rapid selection and proliferation of CD133+ cells from cancer cell lines: chemotherapeutic implications
    Sarah E Kelly
    Department of Biochemistry and Microbiology, Joan C Edwards School of Medicine, Marshall University, Huntington, West Virginia, United States of America
    PLoS ONE 5:e10035. 2010
    ..This could be an important advancement in the therapeutic options of oncologic patients, allowing for more targeted and personalized chemotherapy regimens as well as for higher response rates...
  6. pmc A novel phantom model for mouse tumor dose assessment under MV beams
    Michael S Gossman
    Tri State Regional Cancer Center, Radiation Oncology Department, 706 23rd Street, Ashland, KY 41101, USA
    Health Phys 101:746-53. 2011
    ..The authors fully advocate for treatment planning modeling when possible prior to linac-based dose delivery...
  7. pmc Cadmium induces p53-dependent apoptosis in human prostate epithelial cells
    Pierpaolo Aimola
    Department of Biochemistry and Microbiology, Joan C Edwards School of Medicine, Marshall University, Huntington, West Virginia, United States of America
    PLoS ONE 7:e33647. 2012
    ....