One hundred years ago, in Paul Ehrlich’s laboratory, Sahachiro Hata detected the anti-syphilitic activity of arsphenamine, also known as Salvarsan, during a screening of hundreds of newly synthesized organic arsenic compounds. This drug was the first modern chemotherapeutic agent based on Ehrlich’s ‘magic bullet concept’: drugs that go straight to their intended cell-structural targets. Targeted medicine should in theory efficaciously attack pathogens yet remain harmless in healthy tissues; this idea of selective toxicity has been first principle in the search for more effective treatment against intractable human diseases including cancer. We have been conducting gene therapy for prostate cancer to create a new strategy realizing the ‘magic bullet concept’.

A number of curative treatments are available for patients with localized prostate cancer such as radical prostatectomy, radiotherapy, or brachytherapy. However, there are still no curative therapies for locally advanced, recurrent, or metastatic prostate cancer. Gene therapy provides new therapeutic options; cytoreductive or suicide gene therapy, immunomodulatory gene therapy including cancer vaccine and oncolytic virus therapy are being conducted for prostate cancer. Among them, we have completed a phase I/II study on adenovirus-mediated transduction of the herpes simplex virus thymidine kinase (AdvHSV-tk) gene transfer, followed by a course of the prodrug ganciclovir (GCV), demonstrating clinical safety and efficacy in the treatment of localized hormone refractory prostate cancer (HRPC) (Mol. Ther. 15: 834-40, 2007).

We are now conducting a phase I/II study evaluating adenovirus-mediated Interleukon-12 (AdvIL-12) in situ gene therapy for advanced HRPC. IL-12 is a potent cytokine that demonstrates strong anti-tumor activity, which is derived from many immunomodularoty actions, including IFN-gamma release, expansion and activation of NK and T cells, and differentiation of CD4+cells into Th1 cells. In our preclinical studies using a pre-established metastatic assay, AdvIL-12 in situ gene therapy was found to be effective against local and metastatic tumors (Gene Ther. 6:338-49, 1999).

Telomelysin (OBP-301), a telomerase-specific replication-competent adenovirus with human telomerase reverse transcriptase promoter, is the first product of Oncolys BioPharma, a venture company that was created at Okayama University.  A Phase 1 study for solid tumors will be completed in the USA by the end of this year.  Direct and distant anti-tumor effects of in situ OBP-201 administration have been confirmed in a mouse prostate cancer model (Cancer Gene Ther. 15:315-22, 2008).  

In addition, we are now developing a variety of nanobio-targeted strategies using a novel tumor suppressor gene, REIC/Dkk-3, as an ideal therapeutic gene.  REIC/Dkk-3 (Reduced Expression in Immortalized Cells/Dikkopf-3) was isolated at Okayama University by the representative difference analysis (RDA) system (Biochem Biophys Res Commun. 268:20-4, 2000).  An ideal cancer gene therapy would selectively kill cancer cells without harming normal cells and induce potent 'bystander' anti-tumor effects, facilitating eradication of both primary and metastatic tumors. REIC/Dkk-3 induces cancer-selective apoptosis (Cancer Res. 65: 9617, 2005), stimulates an anti-tumor immune response (unpublished data), sensitizes cancer cells to other modalities of conventional therapies (Cancer Gene Ther. 2008 Jul 25) and exhibits profound 'bystander' activity eliminating both primary and distant tumors in animal models (Cancer Gene Ther. 14:765-72, 2007, unpublished data).

The expression of REIC gene and protein is reduced in a number of immortalized cells and cancer cells and that in Gleason 8 to 10 prostate cancer cells is consistently negative.  Forced expression using adenoviral vector (AdvREIC) selectively induces apoptosis of cancer cells through the activation of the JNK-c-jun pathway mainly due to endoplasmic reticulum (ER) stress (Cancer Res. 2008, in press).  In our orthotopic tumor models with pre-established lung metastases using mouse prostate cancer cell line (RM-9), a single injection of AdvREIC directly into orthotopic prostate tumors demonstrated a dramatic anti-tumor effect on local tumors and increased mean survival time. Significant therapeutic effects on pre-established lung metastases were also observed following the injection of AdvREIC into the orthotopic tumor.  A phase I/II clinical study of AdvREIC in situ gene therapy for HRPC is now being reviewed by the Institutional Review Board. 

The recent studies mentioned above are mainly being conducted at the Innovative Center Okayama for Nanobio-targeted Therapy (ICONT), established within Okayama University in 2006.  ICONT is a unique university and industry cooperative organization supported by the Japanese Government, aiming at “Creation of Innovation Centers for Advanced Interdisciplinary Research Areas”.  Using gene delivery as the core technology, we are creating an innovative nanobio-targeted therapy as a 21st-magic bullet for cancer by integrating the molecular targeting and molecular imaging techniques.