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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Developmental Therapeutics Study Section (DT)
Program Officer
Alley, Michael C
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Virginia Commonwealth University
Schools of Medicine
United States
Zip Code
Sokhi, Upneet K; Bacolod, Manny D; Emdad, Luni et al. (2014) Analysis of global changes in gene expression induced by human polynucleotide phosphorylase (hPNPase(old-35)). J Cell Physiol 229:1952-62
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
Kegelman, Timothy P; Das, Swadesh K; Hu, Bin et al. (2014) MDA-9/syntenin is a key regulator of glioma pathogenesis. Neuro Oncol 16:50-61
Pal, I; Sarkar, S; Rajput, S et al. (2014) BI-69A11 enhances susceptibility of colon cancer cells to mda-7/IL-24-induced growth inhibition by targeting Akt. Br J Cancer 111:101-11
Dash, Rupesh; Bhoopathi, Praveen; Das, Swadesh K et al. (2014) Novel mechanism of MDA-7/IL-24 cancer-specific apoptosis through SARI induction. Cancer Res 74:563-74
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
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
Feng, Qian; Langereis, Martijn A; Lork, Marie et al. (2014) Enterovirus 2Apro targets MDA5 and MAVS in infected cells. J Virol 88:3369-78
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 121:331-82
Das, Swadesh K; Bhutia, Sujit K; Azab, Belal et al. (2013) MDA-9/syntenin and IGFBP-2 promote angiogenesis in human melanoma. Cancer Res 73:844-54

Showing the most recent 10 out of 118 publications