Diphtheria Toxin Gene Therapy Technique Designed to Combat Late-Stage Ovarian Tumors

Particles carrying a killer gene have been shown to effectively suppress ovarian tumor growth in mice, according to a team of researchers.

The findings could lead to a new treatment for ovarian cancer, which now causes more than 15,000 deaths each year in the United States alone. Because it is usually diagnosed at a relatively late stage, ovarian cancer is one of the most deadly forms of the disease.

The new treatment, reported in the August 1, 2009, issue of the journal Cancer Research, delivers a gene that produces the diphtheria toxin, which kills cells by disrupting their ability to manufacture proteins. The toxin is normally produced by the bacterium Corynebacterium diphtheriae.

Human clinical trials could begin, after some additional preclinical studies, in about one year or two, according to Dr. Daniel Anderson, research associate in the David H. Koch Institute for Integrative Cancer Research at the Massachusetts Institute of Technology (MIT; Cambridge, MA, USA) and a senior author of the study.

Currently ovarian cancer patients undergo surgery followed by chemotherapy. In many cases, the cancer recurs after treatment, and there are no good therapies for recurring and advanced-stage tumors. Dr. Anderson and other investigators from MIT, including Institute professor Robert Langer, along with researchers from the Lankenau Institute for Medical Research (Philadelphia, PA, USA), led by Prof. Janet Sawicki, found that the gene-therapy treatment was just as effective, and in some cases more effective, than the traditional chemotherapy combination of cisplatin and paclitaxel. Furthermore, it did not have the toxic side effects of chemotherapy because the gene is engineered to be overexpressed in ovarian cells but is inactive in other cell types.

To additionally ensure tumor-focused effects, the nanoparticles were administered by injection into the peritoneal cavity, which encases abdominal organs such as the stomach, liver, spleen, ovaries, and uterus. Ovarian cancer is known to initially metastasize throughout the peritoneal cavity, and current therapeutic approaches in humans include direct injection into the peritoneal space, thereby targeting the therapy to the ovaries and nearby tissues where tumors may have spread.

The new nanoparticles are made with positively charged, biodegradable polymers known as poly(beta-amino esters). When mixed together, these polymers can spontaneously assemble with DNA to form nanoparticles. The polymer-DNA nanoparticle can deliver functional DNA when injected into or near the targeted tissue.

For several years, the MIT-Lankenau team has been developing these nanoparticles as an alternative to viruses, which are associated with safety risks. In addition to ovarian cancer, these nanoparticles have demonstrated potential for treatment of a variety of diseases, including prostate cancer and viral infection. "I'm so pleased that our research on drug delivery and novel materials can potentially contribute to the treatment of ovarian cancer,” Dr. Langer said.

In future research, the team plans to examine the effectiveness of nanoparticle-delivered diphtheria toxin genes in other types of cancer, including lung, brain, and liver cancers.

Related Links:
Massachusetts Institute of Technology
Lankenau Institute for Medical Research