Researchers identify mechanism used by therapeutically active antitumor cytokine gene able to induce potent bystander antitumor effect in cancer cells

By Anne Buckley

Keywords: antitumor effect, mda-7/IL-24, endoplasmic reticulum stress

Research Highlights:

• Molecular and biochemical mechanism of action of unique cytokine gene found to induce potent bystander antitumor effects in animal models and in Phase I clinical trials identified
• The findings may lead researchers to develop potential novel enhanced therapies to treat various forms of cancer

Virginia Commonwealth University and VCU Massey Cancer Center researchers have uncovered how a gene, melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24), induces a bystander effect that kills cancer cells not directly receiving mda-7/IL-24 without harming healthy ones, a discovery that could lead to new therapeutic strategies to fight metastatic disease.
 
The findings may provide a method to target metastatic disease – which is one of the primary challenges in cancer therapy. When cancer cells are localized in the body, specialists may be able to surgically remove the diseased area. However, when cancer metastasizes or spreads to sites remote from the primary tumor through the lymph system and blood vessels to new target sites, treatment becomes more difficult and in many instances ineffective. 

In the study, published online in the June 30 issue of the Proceedings of the National Academy of Sciences, researchers report on the molecular and biochemical mechanisms by which the gene, mda-7/IL-24, is able to selectively kill cancer cells through apoptosis, or programmed cell death. The gene induces a potent bystander effect, meaning that it not only kills the original tumor, but distant ones as well, which has been observed but previously not mechanistically defined in animal models containing human cancers and in a Phase I Clinical Trial involving direct injection of an adenovirus expressing mda-7/IL-24 into advanced carcinomas and melanomas.

Further, the team determined that mda-7/IL-24 induces tumor-specific killing through a process known as endoplasmic reticulum stress. The endoplasmic reticulum, or ER, is a subcellular structure that plays a key role in cellular protein disposition. ER stress results from accumulation of extra proteins in the ER of a cancer cell and can activate pro-survival or pro-cell suicide pathways.

"Cancer cells cannot accommodate or recover from stress the way normal, healthy cells can. When the ER is stressed in this way, the result is an unfolded protein response which overloads the system and shorts out the cancer cell. This prevents tumor development, growth and invasion – and ultimately the cancer cell dies," said Paul B. Fisher, Ph.D., professor and interim chair of the Department of Human and Molecular Genetics, and director of the VCU Institute of Molecular Medicine, in the VCU School of Medicine.

This work was supported by grants from the National Institutes of Health and the Samuel Waxman Cancer Research Foundation.

In related work, Fisher, who is the first incumbent of the Thelma Newmeyer Corman Endowed Chair in Cancer Research and researcher with the VCU Massey Cancer Center, has been invited by the NIH's National Cancer Institute to present his team's translational research on mda-7/IL-24 at the National Cancer Institute's (NCI) Translational Science Meeting. The research focuses on using mda-7/IL-24 in the development of therapies for prostate cancer, malignant glioma and ovarian cancer. The meeting is scheduled for November 2008 in Washington, D.C.

Fisher worked with a team that included VCU School of Medicine researchers Paul Dent, Ph.D., professor in the VCU Department of Biochemistry and Molecular Biology; Zaozhong Su, Ph.D., associate professor in the VCU Department of Human and Molecular Genetics; Devanand Sarkar, Ph.D., assistant professor at the VCU Massey Cancer Center and Department of Human and Molecular Genetics; and Moira Sauane, Ph.D.; Pankaj Gupta, Ph.D.; and Irina V. Lebedeva, Ph.D., with the Columbia University College of Physicians and Surgeons in New York.