966. Synergy between Angiostatin-Endostatin and Tie-2: A Novel Anti-Angiogenic Gene Therapy for Prostate Cancer

Abstract

Prostate cancer (CaP) is the most frequently diagnosed cancer in men and the second leading cause of cancer related deaths in American men. In 2003, CaP was expected to account for 220,900 cancer diagnoses and 28,900 cancer deaths. Despite recent advances in the early detection and treatment of locally advanced prostate cancer, the prognosis for patients with the advanced form of prostate cancer is grave. Although a majority of patients with advanced prostate cancer respond initially to androgen ablation therapy, an emergence of the hormone refractory form of the disease, in the absence of continued androgenic stimulation, with widespread metastasis and a fatal outcome is inevitable. Considering the fact that both tumor growth an metastasis are dependent upon angiogenesis, the use of agents that inhibit the generation of new blood vessels represents a potential therapeutic approach for cancer gene therapy. Angiostatin, endostatin and the soluble form of Tie-2 extracellular domain have been shown to be one of the most potent endogenous angiogenesis inhibitors. Since these anti-angiogenic agents operate through different molecular mechanisms, their combination may result in potentially synergistic effects. Towards this goal, we have developed replication defective adenoviral vectors Ad-hEndo-angio, expressing a novel, chimeric endostatin-angiostatin protein and Ad-sTie-2 expressing the soluble form of Tie-2 receptor extracellular domain. We have investigated the anti-angiogenic effects mediated by these vectors either separately or their combination in an androgen independent subcutaneous human PC-3 prostate tumor model following intra-tumoral and systemic delivery. Our in vivo results reveal significant suppression of tumor angiogenesis and inhibition of tumor growth following both intra-tumoral and systemic delivery of Ad-hEndo-angio and Ad-sTie-2 vectors. Further, Ad-hEndo-angio was capable of generating a much more potent anti-angiogenic and anti-tumor effect as compared to Ad-sTie-2. Next we investigated whether a combination of Ad-hEndo-angio and Ad-sTie-2 vectors, each using half the dose following intra-tumoral delivery only in one tumor can inhibit tumor growth and angiogenesis of the tumor on the contralateral side. Our results indicate that this modality resulted in complete tumor eradication on both the sides. These animals have remained tumor free for more than nine months now. Our attempts to challenge these mice with subcutaneous injection of PC-3 cells have failed to generate any tumor during the entire course of the study. To the best of our knowledge, this is the first study of its kind to provide novel insights into the synergistic mode of anti-angiogenic activity in general and will lead to the development of novel anti-angiogenic gene therapy approaches for prostate cancer.