Melanoma differentiation associated gene-7 (mda-7)/IL-24: a ‘magic bullet’ for cancer therapy?

Abstract

An ideal cancer gene therapy would selectively kill cancer cells without harming normal cells and induce multipronged ‘bystander’ antitumor effects, facilitating eradication of both primary and metastatic tumors. Melanoma differentiation associated gene-7 (mda-7)/interleukin-24 (IL-24) exhibits all of these attributes and more. It induces cancer-selective apoptosis, inhibits angiogenesis, stimulates an antitumor immune response, sensitizes cancer cells to radiation and other modalities of conventional therapies, and exhibits profound ‘bystander’ activity eliminating both primary and distant tumors in animal models. Moreover, a replication-incompetent adenovirus expressing mda-7/IL-24, Ad.mda-7 (INGN-241), has now undergone evaluation in a Phase I clinical trial for multiple solid tumors, including melanomas, and has demonstrated safety and significant objective clinical activity. Considering these exciting observations, mda-7/IL-24 is being hailed as a ‘magic bullet’ for cancer gene therapy. This review elaborates on the pleiotropic properties of mda-7/IL-24 and unravels novel aspects of the molecule mandating future studies and expanded clinical applications.

Keywords::

• antiangiogenesis
• antitumor agents
• bipartite adenovirus
• bystander antitumor activity
• cancer-selective apoptosis
• conditional replication-competent adenovirus
• ER stress
• IL-10 family member
• immune modulation
• radiosensitization
• reactive oxygen species

Acknowledgements

The present studies were supported in part by NIH grants R01 CA35675, R01 CA97318, R01 CA98712 and P01 CA104177, Army DOD grant DAMD17-03-1-0290, the Lustgarten Foundation for Pancreatic Cancer Research, the Samuel Cancer Research Foundation and the Chernow Endowment. The author is the Michael and Stella Chernow Urological Cancer Research Scientist and a SWCRF Investigator.

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