Despite intensive research, no single therapeutic approach has proven very successful in effecting a long-term cure of prostate cancer, even when disease is initially detected as a localized focus. Androgen ablation, prostatectomy or radiotherapy are at best palliative and have drastic consequences on post-treatment quality of life. Current statistics indicate a high frequency of recurrence accompanied by aggressive metastasis within relatively short periods after radical therapeutic intervention. A gene therapy based approach represents promising alternative therapeutic prospects in the prevailing scenario of limited survival benefits with conventional treatment. Subtraction hybridization identified a novel gene, melanoma differentiation associated gene-7. Based on structural and functional homology to interleukin-10, mda-7 has been recently redesignated as IL-24. mda-7/IL24 when expressed by means of a replication incompetent adenovirus, Ad.mda-7, suppresses growth and reduces viability by inducing apoptosis in a broad spectrum of cancers, including prostate carcinomas. In contrast, Ad.mda-7 does not produce harmful effects in a spectrum of normal cell types. These observations have been extended to the clinical setting indicating that Ad.mda-7 is safe and a single intratumoral injection in patients with advanced carcinomas and melanomas results in apoptosis in a high percentage (> 70%) of the tumor and repeated doses have produced objective clinical responses. As seen with Ad.mda-7, purified GST-MDA-7 fusion protein also induces apoptosis when applied to cancer cells, including prostate carcinomas, but not to normal cells. These unique cancer-specific apoptosis inducing properties suggest that mda-7/IL-24 is a strong candidate cancer gene therapeutic for treatment of primary prostate tumors as well as metastases. Understanding the mechanism by which mda-7/IL-24 induces its anti-prostate carcinoma specific effect will define ways of enhancing its activity, determining safety parameters and thereby facilitate the likelihood of transferring this molecule into the clinic for this cancer. Based on very promising recent findings, studies will be performed to:
Specific Aim 1 : Investigate the basis of mda-7/IL-24 prostate cancer specific apoptosis inducing properties. Experiments will define structure/function relationships through mutagenesis. Given the potentially central role of BCL-2 and BCL-xL in prostate cancer development, we will determine their importance in regulating sensitivity of prostate carcinoma cells to mda 7/IL-24. Experiments will be performed in collaboration with Dr. Dent (Project 2) to define the role of specific signal transduction pathways and ionizing radiation in regulating Ad.mda-7 protein mediated induction of apoptosis in prostate cancer cells.
Specific Aim 2 : Develop a novel, innovative gene therapy approach that will enhance the clinical utility of mda-8/IL-24 for the therapy of prostate cancer. A novel Triage Virus will be made in collaboration with Dr. Curiel. (Project 3, CoreB)with modified infectivity properties resulting from fiber/penton modifications (complex mosaic), prostate cancer-specific replication using the progression elebated gene-3 promoter (PEG-Prom) to drive E1A/E1B viral gene expression and expression of mda-7/IL-24 as a function of virus replication uniquely in prostate cancer cells.
Specific Aim 3 : Evaluate pre-clinical utility of conditionally replicating adenoviruses(CRAds) and infectivity enhanced conditionally replicating adenoviruses (IE-CRAds)(complex mosaic) in the context of a metastatic prostate cancer model in athymic nude mice. In summary, the proposed studies in this component of the program project will provide insights into the mechanism of action of a novel cancer specific apoptosis inducing cytokine, mda-7/IL-24, in the context of prostate cancer. Moreover, these experiments will provide a basis for future translational studies using this gene and its protein, alone or in combination with radiation, as an improved therapy for primary and metastatic prostate cancers.
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