Application for PTEN Gene Therapy in Prostate Cancer

2004 Fiscal Year Final Research Report Summary

• Project/Area Number: 15591709
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Urology
• Research Institution: Nara Medical University School of Medicine
• Principal Investigator: TANAKA Motoyoshi Nana Medical Univ., Dept.of Urology, Instructor, 医学部・泌尿器科学, 助手 (30347562)
• Co-Investigator(Kenkyū-buntansha): HIRAO Yoshihiko Nana medical Univ., Dept.of Urology, Professor, 医学部・泌尿器科, 教授 (00133207) ; KONISHI Noboru Nara Med.Univ., Dept.of Pathology, Professor, 医学部・病理病態, 教授 (20145832) ; UEMURA Hirotsugu Kinki Univ., Dept.of Urology, Professor, 泌尿器科, 教授 (90213397)
• Project Period (FY): 2003 – 2004
• Keywords: Prostate cancer / PTEN tumor suppressor gene / gene therapy

Research Abstract

We have demonstrated that an adenoviral gene therapy of PTEN can effectively treat bladder and prostate cancers, and can be effectively treated tumors which exhibit drug or radiation resistance associated with expression of phosphorylated Akt in combination with chemotherapy or radiotherapy. PTEN is well known as a tumor suppressor gene and has a phosphatase activity in the phosphatidylinositol 3'-kinase mediated signal transduction pathway and inhibits the activation of Akt, a serine-threonine kinase involved in proliferative and anti-apoptotic pathways. These days, using virus vector for cancer gene therapy is controversial, and non-viral gene transfer is a future promising procedure but several problems need to be cleared, such as transduction efficacy. We have developed non-viral compound conjugated with cationized gelatin microsphere and plasmid DNA, which is a new type of gene transfer drug and designed to release plasmid DNA and last the gene expression continuously for a long p eriod in vivo. In this study, we originally generated the GelaTen, which is a conjugate with cationized gelatin microsphere (2 mg) and PTEN expression vector (100 μg), and examined the efficacy of GelaTen as a combination therapy with radiation in prostate cancer. Single direct injection of GelaTen into established subcutaneous bcl-2-overexpressing PC3 prostate cancer tumors (PTEN deleted, up-regulation of phosphorylated Akt and Bcl-2) in nude mice, which reached approximately 5-7mm in diameter, resulted in significantly decreased growth compared to the conjugate with ss-gal plasmid (control) or PBS treated tumors. Immunohistochemical analysis showed that tumors inducted with GelaTen expressed PTEN and exhibited decreased amounts of phosphorylated Akt, whereas tumors treated with CTL or PBS were negative for PTEN and diffusely positive for phosphorylated Akt. Since PTEN downregulates phosphorylated Akt and Bcl-2 and increases sensitivity to radiation, we explored combination therapy with GelaTen and radiation in vivo. Combination therapy with GelaTen and 5 Gy irradiation (5 days after GelaTen injection) improved the in vivo efficacy of tumor growth compared to the GelaTen monotherapy alone in these tumors. These data demonstrate that PTEN gene therapy with gene drug GelaTen can effectively treat prostate cancers that have genomic alterations in PTEN. Furthermore, tumors that exhibit radiation resistance associated with expression of phosphorylated Akt and Bcl-2 can be effectively treated with GelaTen and radiotherapy.