title: Developing an effective gene therapy for prostate cancer: New technologies with potential to translate from the laboratory into the clinic.
abstract: Prostate cancer is the second leading cause of cancer-related deaths in men in the U.S. At present, no single or combination therapy has shown efficacy in decreasing disease progression in patients with metastatic disease. A potentially viable approach for treating late-stage prostate cancer is gene therapy. Adenoviruses (Ad) are the most commonly used mode of gene delivery, but progress using this vector has been hampered by concerns over the safety and practicality of viruses including conditionally replicating Ads (CRAds), particularly for intravenous delivery, and the inefficiency of non-viral transfection techniques. Major challenges for effective gene therapy using Ads are the limited infectivity of regular Ad serotype 5 (Ad5) and the inability to specifically deliver the therapeutic directly into diseased tissue without trapping in the liver or elimination by the immune system. The shortcoming in using Ad5 is mostly attributed to a reduction in Coxsackie-adenovirus receptors (CAR) on the surface of cancer cells, which can be mitigated by generating tropism-modified Ads permitting CAR-independent infection of tumor cells. The limitations of systemic gene delivery can now be overcome by using a novel targeted-delivery approach such as ultrasound (US) contrast agents (microbubbles) to deliver effective therapeutic reagents, Ads, or recombinant proteins, combined with ultrasound-targeted microbubble destruction (UTMD), to develop a site-specific therapy in immune competent transgenic mouse models. These unique strategies for enhancing the efficacy of gene therapy provide a direct path to translation from the laboratory into the clinic for developing an effective gene therapy of prostate cancer.
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, 23298, USA.
authors.forename: Rupesh
authors.initials: R
authors.lastname: Dash
authors.forename: Belal
authors.initials: B
authors.lastname: Azab
authors.forename: Xue-Ning
authors.initials: XN
authors.lastname: Shen
authors.forename: Upneet K
authors.initials: UK
authors.lastname: Sokhi
authors.forename: Siddik
authors.initials: S
authors.lastname: Sarkar
authors.forename: Zhao-zhong
authors.initials: ZZ
authors.lastname: Su
authors.forename: Xiang-Yang
authors.initials: XY
authors.lastname: Wang
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Claudio
authors.forename: Paul
authors.initials: P
authors.lastname: Dent
authors.forename: Igor P
authors.initials: IP
authors.lastname: Dmitriev
authors.forename: David T
authors.initials: DT
authors.lastname: Curiel
authors.forename: Steven
authors.initials: S
authors.lastname: Grant
authors.forename: Devanand
authors.initials: D
authors.lastname: Sarkar
authors.forename: Paul B
authors.initials: PB
authors.lastname: Fisher
mesh_terms: D000256:Adenoviridae / Q000276:immunology; D000818:Animals; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D008297:Male; D045423:Microbubbles; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000628:therapy*; D057170:Translational Research, Biomedical / Q000379:methods*