Conventional therapies, including surgery coupled with chemotherapy, have not resulted in significant improvements in overall survival rates for ovarian cancer. In this context, novel therapeutic modalities are required for this disease. Gene therapy represents a rational and potentially effective approach for ovarian carcinoma. To this end, a number of distinct cancer gene therapy approaches have been developed for ovarian carcinomas, which are predicated upon direct gene delivery to tumor cells. To achieve effective gene delivery, recombinant adenoviral vectors have been employed based on their superior in vivo efficacy characteristics. Whereas adenoviral vectors are understood to exhibit superior levels of in vivo gene transfer compared to available alternative vector systems, present levels may nonetheless be sub optimal for ovarian cancer gene therapy applications. On this basis, we have endeavored to modify the tropism of adenoviral vectors to achieve enhanced gene delivery to tumor cells as a means to improve the overall feasibility of these cancer gene therapy strategies. We have achieved adenovirus retargeting using genetic strategies to alter tropism. In the present proposal, we seek to further develop these approaches to allow the development of adenoviral vectors, which allow maximal enhancement of gene delivery to ovarian cancer cells. With this objective in mind, we have developed a highly novel strategy of Ad tropism alteration whereby multiple, and distinct, retargeting ligands are genetically incorporated into the viral capsid """"""""complex mosaic"""""""". The ability to achieve biological access to multiple cellular entry pathways potentially allows for maximized gene delivery to tumor cells deficient in the primary Ad receptor. We hypothesize that these """"""""complex mosaic"""""""" adenoviral vectors will allow the achievement of an improved therapeutic index in the context of mda-7/IL-24 based gene therapy approaches for ovarian carcinoma. In principle, these """"""""complex mosaic"""""""" adenoviral vectors should also prove beneficial for treatingother cancers, including prostate cancer (Project 1: Fisher) and malignant glioma (Project 2: Dent). This strategy may also be amenable to increase the infectivity of adenoviral vectrs in which replication is restricted to cancer cells by the progression elevated gene-3 promoter and mda-7/IL-24 is expressed in a different region of the adenoviral genome (proposed in Project 1:Fisher). This vector would provide a direct means of enforcing replication in cancer cells resulting in their cytolysis with concomitant production of mda-7/IL-24. Such a """"""""complex mosaic"""""""" adenoviral vector would offer profound cancer specific activity, not only in ovarian, but also in other cancers and be of direct relevance to the theme of this program project, to increase the translational aspects of mda- 7/IL-24 for cancer therapy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA104177-03
Application #
7487898
Study Section
Subcommittee G - Education (NCI)
Project Start
Project End
Budget Start
2007-09-01
Budget End
2008-08-31
Support Year
3
Fiscal Year
2007
Total Cost
$352,943
Indirect Cost
Name
Columbia University (N.Y.)
Department
Type
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
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

Showing the most recent 10 out of 155 publications