Mda-7/IL-24 exemplifies the ideal cancer gene therapeutic. It induces apoptosis selectively in diverse cancer cells without exerting deleterious effects to their normal counterparts, inhibits angiogenesis, stimulates an anti-tumor immune response, sensitizes cancer cells to other conventional modalities of therapy and exhibits profound 'bystander'anti-tumor activity eliminating both primary and distant tumors in animal models. Moreover, a replication incompetent adenovirus expressing mda-7/IL-24, Ad.mda-7, has been evaluated in a Phase I clinical trial for multiple solid tumors and melanomas demonstrating safety and significant objective anti-tumor clinical response. However, despite these intriguing properties, the mechanism(s) underlying the selective activity of this novel cytokine toward cancer cells remains to be defined. mda-7/IL-24 exhibits two modes of killing. As a secreted cytokine it binds to its cognate receptors and mediates anti-angiogenic, radiosensitization, immunostimulatory and 'bystander'activities. Alternatively, MDA-7/IL-24 protein, delivered by Ad.mda-7, localizes to the endoplasmic reticulum, interacts with the ER chaperone protein GRP78/BiP and generates an ER stress response. Additionally, Ad.mda-7 generates reactive oxygen species (ROS) in mitochondria and activates an apoptotic signaling cascade and also generates ceramide, a known inducer of apoptosis. All these phenomena, ER stress response, ROS and ceramide generation, are observed in the same human prostate cancer cells. However, these fragmented observations have not been linked by a unified molecular mechanism of action. The mechanism of 'bystander'activity also remains to be elucidated. Preliminary studies reveal that recombinant MDA-7/IL-24 protein induces expression of endogenous mda-7/IL-24. Accumulation of intracellular MDA-7/IL-24 might be a potential molecular mechanism for the 'bystander'effect providing a convergence between extracellular and intracellular tumor-specific apoptotic activities of this cytokine. We propose an in-depth analysis of molecular pathways of mda-7/IL-24 action, including its 'bystander'activity, to provide better insight into how this pleiotrophic tumor suppressor protein works. The information garnered will facilitate development of strategies to augment the anti-tumor effects of mda-7/IL-24. Considering the fact that Ad.mda-7 is already showing promise in clinical studies, successful completion of the proposed studies will significantly augment the therapeutic applications of mda-7/IL-24 potentially leading to elimination of both primary and metastatic tumors.

Public Health Relevance

Melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24) is a novel secreted cytokine belonging to the IL-10 gene family that has the unique property of selectively inducing apoptosis in diverse cancer cells without harming normal cells or tissues. Additionally, secreted MDA-7/IL-24 protein generates a profound 'bystander'anti-tumor activity significantly enhancing its therapeutic properties. The present proposal aims at elucidating the molecular mechanism by which mda-7/IL-24 exerts its pleiotrophic effects as a cancer therapeutic. The studies we propose will provide valuable information that can be used to define rational approaches for enhancing the cancer therapy applications of mda-7/IL-24.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA097318-10
Application #
8270570
Study Section
Developmental Therapeutics Study Section (DT)
Program Officer
Alley, Michael C
Project Start
2002-09-10
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2014-05-31
Support Year
10
Fiscal Year
2012
Total Cost
$259,625
Indirect Cost
$85,963
Name
Virginia Commonwealth University
Department
Genetics
Type
Schools of Medicine
DUNS #
105300446
City
Richmond
State
VA
Country
United States
Zip Code
23298
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/PKCδ Signaling Axis. J Biol Chem 291:21669-21681
Bhoopathi, Praveen; Lee, Nathaniel; Pradhan, Anjan K et al. (2016) mda-7/IL-24 Induces Cell Death in Neuroblastoma through a Novel Mechanism Involving AIF and ATM. Cancer Res 76:3572-82
Menezes, M E; Das, S K; Minn, I et al. (2016) Detecting Tumor Metastases: The Road to Therapy Starts Here. Adv Cancer Res 132:1-44
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
Menezes, Mitchell E; Shen, Xue-Ning; Das, Swadesh K et al. (2015) MDA-7/IL-24 functions as a tumor suppressor gene in vivo in transgenic mouse models of breast cancer. Oncotarget 6:36928-42
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
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
Bhatia, Shilpa; Emdad, Luni; Das, Swadesh K et al. (2014) Non-BRAF targeted therapies for melanoma: protein kinase inhibitors in Phase II clinical trials. Expert Opin Investig Drugs 23:489-500
Menezes, Mitchell E; Bhatia, Shilpa; Bhoopathi, Praveen et al. (2014) MDA-7/IL-24: multifunctional cancer killing cytokine. Adv Exp Med Biol 818:127-53

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