Translational Applications of mda-7/IL-24 in Cancer

DESCRIPTION (provided by applicant): The long-term objectives of our research programs are to develop an improved understanding and define enhanced translational applications for a novel gene, mda-7/IL-24, with significant clinical potential as an anticancer gene therapeutic. Subtraction hybridization identified the cancer-selective apoptosis-inducing cytokine gene, mda-7/IL-24, which displays antiproliferative and programmed cell death promoting activities in a wide spectrum of histologically distinct human cancers. In contract, mda-7/IL-24 produces no harmful effects in normal cells. Based on these promising attributes, Phase I/II clinical trials were performed to assess safety of mda-7/IL-24 in patients. When administered intratumorally in patients with advanced carcinomas and malignant melanomas by means of a replication incompetent adenovirus, Ad.mda-7 (INGN 241) was shown to be safe, without significant side effects, and to induce apoptosis in a majority of the tumor mass after a single injection of virus. These exciting findings provide support for aggressively evaluating mda-7/IL-24 for cancer gene therapy. The specific aims of this PPG are to expand on the provocative basic science studies and the early clinical successes of mda-7/IL-24 to accelerate its translational applications in three cancer indications, prostate cancer, glioblastoma multiforme and ovarian cancer. To achieve these objectives, a team of established investigators has been assembled with documented experience in cancer cell biology, cancer gene therapy, oncology and radiation biology. Support is requested for definitive studies that will lead to improved translational applications of mda-7/IL-24 in prostate, glioblastoma multiforme and ovarian cancer. We are also requesting administrative support for the Program Project and support for two core resource facilities, one for producing purified MDA-7/IL-24 protein (which like the gene display cancer-specific apoptosis inducing properties) and one for producing genetically engineered viruses expressing mda-7/IL-24, to facilitate studies by members of the Program Project team. The individual interactive projects and cores and their objectives are: Project 1: Develop improved therapeutic applications of mda-7/IL-24 in prostate cancer. This project will focus on defining regions of mda-7/IL-24 mediating its apoptosis inducing effects;developing improved methods for delivering and expressing mda-7/Il-24 in prostate cancer cells;and preclinical animal studies to define potential efficacy of new infectivity enhanced viruses targeting prostate cancer cells and producing mda-7/IL-24. (Fisher) Project 2: Develop improved therapeutic applications of mda-7/IL-24 in malignant gliomas. This project will focus on defining the mechanism by which MDA-7 protein and Ad.mda-7 radiosensitize human malignant gliomas to lose viability and to determine preclinical efficacy in pre-existing tumors in the rat brain. (Dent) Project 3: Develop improved "complex mosaic" adenoviruses to improved delivery of mda-7/IL-24 into and study the effects on ovarian cancer cells in vitro and in vivo in nude mice. (Curiel) Core A: Produce purified MDA-7 protein for mechanistic studies proposed in Projects 1, 2 and 3. (Gupta) Core B: Produce recombinant adenoviruses for mechanistic studies proposed in Projects 1, 2 and 3. (Curiel) Core C: To provide administrative support for this program project grant. (Fisher)