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Anne Buckley
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Researchers identify mechanism used by therapeutically active anti-tumor cytokine gene able to induce potent bystander anti-tumor effect in cancer cells

Research highlights:

Molecular and biochemical mechanism of action of unique cytokine gene found to induce potent bystander anti-tumor 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

RICHMOND, Va. (June 30, 2008) – 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 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 and Harrison Scholar in Cancer Research 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.

Editor’s note: A copy of the study is available for reporters by e-mail request from pnasnews@nas.edu.

About VCU and the VCU Medical Center: Virginia Commonwealth University is the largest university in Virginia and ranks among the top 100 universities in the country in sponsored research. Located on two downtown campuses in Richmond, VCU enrolls nearly 32,000 students in 205 certificate and degree programs in the arts, sciences and humanities. Sixty-five of the programs are unique in Virginia, many of them crossing the disciplines of VCU’s 15 schools and one college. MCV Hospitals and the health sciences schools of Virginia Commonwealth University compose the VCU Medical Center, one of the nation’s leading academic medical centers. For more, see www.vcu.edu.

About the VCU Massey Cancer Center: The VCU Massey Cancer Center is one of 63 National Cancer Institute-designated institutions that leads and shapes America’s cancer research efforts. Working with all kinds of cancers, the Center conducts basic, translational and clinical cancer research, provides state-of-the-art treatments and clinical trials, and promotes cancer prevention and education. Since 1974, Massey has served as an internationally recognized center of excellence. It offers more clinical trials than any other institution in Virginia, serving patients in Richmond and in four satellite locations. Its 1,000 researchers, clinicians and staff members are dedicated to improving the quality of human life by developing and delivering effective means to prevent, control and ultimately to cure cancer. Visit Massey online at www.massey.vcu.edu or call 1-877-4-MASSEY.