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)

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
7P01CA104177-04
Application #
7487901
Study Section
Subcommittee G - Education (NCI)
Program Officer
Muszynski, Karen
Project Start
2005-09-19
Project End
2010-08-31
Budget Start
2008-09-01
Budget End
2009-08-31
Support Year
4
Fiscal Year
2008
Total Cost
$1,329,682
Indirect Cost
Name
Virginia Commonwealth University
Department
Genetics
Type
Schools of Medicine
DUNS #
105300446
City
Richmond
State
VA
Country
United States
Zip Code
23298
Menezes, Mitchell E; Bhoopathi, Praveen; Pradhan, Anjan K et al. (2018) Role of MDA-7/IL-24 a Multifunction Protein in Human Diseases. Adv Cancer Res 138:143-182
Pradhan, Anjan K; Emdad, Luni; Das, Swadesh K et al. (2017) The Enigma of miRNA Regulation in Cancer. Adv Cancer Res 135:25-52
Shapiro, Brian A; Vu, Ngoc T; Shultz, Michael D et al. (2016) Melanoma Differentiation-associated Gene 7/IL-24 Exerts Cytotoxic Effects by Altering the Alternative Splicing of Bcl-x Pre-mRNA via the SRC/PKC? Signaling Axis. J Biol Chem 291:21669-21681
Bacolod, Manny D; Das, Swadesh K; Sokhi, Upneet K et al. (2015) Examination of Epigenetic and other Molecular Factors Associated with mda-9/Syntenin Dysregulation in Cancer Through Integrated Analyses of Public Genomic Datasets. Adv Cancer Res 127:49-121
Talukdar, Sarmistha; Emdad, Luni; Das, Swadesh K et al. (2015) Noninvasive approaches for detecting and monitoring bladder cancer. Expert Rev Anticancer Ther 15:283-94
Kegelman, Timothy P; Das, Swadesh K; Emdad, Luni et al. (2015) Targeting tumor invasion: the roles of MDA-9/Syntenin. Expert Opin Ther Targets 19:97-112
Sarkar, Siddik; Quinn, Bridget A; Shen, Xuening et al. (2015) Reversing translational suppression and induction of toxicity in pancreatic cancer cells using a chemoprevention gene therapy approach. Mol Pharmacol 87:286-95
Das, Swadesh K; Menezes, Mitchell E; Bhatia, Shilpa et al. (2015) Gene Therapies for Cancer: Strategies, Challenges and Successes. J Cell Physiol 230:259-71
Azab, Belal M; Dash, Rupesh; Das, Swadesh K et al. (2014) Enhanced prostate cancer gene transfer and therapy using a novel serotype chimera cancer terminator virus (Ad.5/3-CTV). J Cell Physiol 229:34-43
Menezes, Mitchell E; Das, Swadesh K; Emdad, Luni et al. (2014) Genetically engineered mice as experimental tools to dissect the critical events in breast cancer. Adv Cancer Res 121:331-382

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