Effective Advanced-Stage Ovarian Cancer Treatment May Soon Be Possible

Ovarian cancer is the fifth most deadly cancer in women. This is due primarily to the fact the disease is generally not diagnosed until after it has entered advanced stages. In addition, no matter when the diagnosis is made, ovarian cancer has a high rate of recurrence after initial treatment. As there are currently no effective treatments for recurring ovarian cancer or late-stage tumors, this leaves us with the American Cancer Society estimating 14,600 deaths from the disease during 2009. The number increases to approximately 140,000 deaths when expanded to a global scale.

Researchers from the Lankenau Institute for Medical Research, Pennsylvania, and the Massachusetts Institute of Technology, have now addressed the issue of recurrent and advanced stage treatment. They have developed a nanoparticle-delivered suicide gene therapy that has suppressed advanced stage ovarian cancer tumors in mice. Their findings were published on Thursday, July 29, 2009, in the August 2009 issue of the medical journal Cancer Research.

The Current Prognosis for Ovarian Cancer Patients
Ovarian cancer is so deadly due to the difficulty in diagnosing the disease. Most ovarian cancer tumors are too small to detect in the early stages. Added to that, the disease usually does not produce noticeable symptoms until it has already entered advanced stages. In an unrelated study by Howard Hughes Medical Institute researchers, it was discovered ovarian cancer is active in the body for an average of nine years before it is clinically diagnosed and has already been in late stages for more than a year by that time. This late discovery is of major concern due to the fact there are currently no effective therapies for patients with advanced ovarian cancer.

In an interview discussing the new suicide gene therapy, lead researcher Janet Sawicki, Ph.D., a professor at the Lankenau Institute for Medical Research, gave the following prognosis for ovarian cancer patients:

• 20% of ovarian cancer patients who are treated through surgery and chemotherapy will not respond to therapy.
• While 80% of ovarian cancer patients do respond to initial treatments, the majority will develop recurrent tumors. The recurrent tumors are due to the women developing resistance to the chemotherapeutics commonly used during treatment.
• 50%-60% of the women who develop recurrent tumors will die from their ovarian cancer.
• The overall five-year rate of survival for women with ovarian cancer is around 42%.

"There is a real need for a better and more effective therapy," said Dr. Sawicki.

A Better and More Effective Therapy for Ovarian Cancer
The new technology developed by Dr. Sawicki and her colleagues uses nanoparticles containing DNA encoding a diphtheria toxin suicide protein.

Nanoparticles are created by combining a polymer with DNA. In this case, the researchers used a cationic (positively charged) biodegradable beta-amino ester polymer and diphtheria toxin DNA. Once combined, the DNA condenses and forms a nanoscale (one-millionth of a millimeter) particle. The nanoparticle can then be injected into or near the desired tissue, where it will bind to and enter the ovarian cancer tumor cells. This form of therapy promises to provide a cancer treatment that only destroys specific cells, unlike standard chemotherapy treatments that cause damage to healthy and unhealthy cells. Scientists at the Davide H. Koch Institute for Integrative Cancer Research at MIT, where a significant amount of nanoparticle research is done, refers to them as "smart bombs" for cancer.

The diphtheria toxin that Dr. Sawicki and her colleagues used is a genetically altered version of the toxin that causes diphtheria disease. The genetic alterations remove the threat of disease by instructing the toxin to infect only ovarian cancer tumor cells, not the healthy cells surrounding the tumor. Once the altered DNA enters a tumor cell, it produces the diphtheria toxin. The toxin and protein synthesis within the cell shuts down. As all cells require protein to survive, removing the ability to produce protein means the ovarian cancer tumor cell will die.

The nanoparticles containing the diphtheria toxin suicide gene were tested in laboratory mice with primary or metastatic ovarian tumors. The researchers than compared the nanoparticle treated mice with control mice.

Their findings included:

• The tumors of the control mice showed a 4.1-fold to 6-fold increase during the test period. The tumors of the injected mice only showed up to a 2-fold increase.
• Four of the nanoparticle treated tumors showed no growth at all. All tumors in the control mice increased in size.
• Three of the injected mice had a prolonged lifespan of up to four weeks beyond the untreated control mice.
• The nanoparticle treated mice showed minimal healthy cell and blood chemical toxicity, unlike the control mice that were treated with standard chemotherapy drugs.

Speaking of these results, Janet Sawicki said, "This report is definitely a reason to hope. We now have a potential new therapy for the treatment of advanced ovarian cancer that has promise for targeting tumor cells and leaving healthy cells healthy."

The researchers hope to start human testing within 18 to 24 months.