Stanford Report, September 27, 2000
|Designer vaccines, thalidomide provide hope for battling
BY CHARLES CLAWSON
With the goal of transforming ovarian cancer from a deadly malignancy to a chronic but treatable disease, Stanford researchers are exploring a variety of new treatments, such as cutting off a cancer's blood supply or "programming" into the cancer its cellular death.
September is National Gynecologic/Ovarian Cancer Awareness Month, with the intent of raising awareness of this "silent killer." Ovarian cancer often remains undetected until an advanced stage, when it has spread beyond the ovaries. Its mild symptoms include pressure or fullness in the pelvis, abdominal bloating, or changes in bowel patterns that are constant and progressive. This year 14,000 women in the United States are expected to die from the disease.
Stanford researchers are hopeful that studies currently under way will contribute to lowering that number.
One Stanford study focuses on a gene called P53, which works naturally to suppress tumor formation. In ovarian cancer a large percentage of these genes become mutated and fail to produce their normal tumor-suppressing chemical. Current thought is that this failure allows the cancer to form.
James Roberts, MD, a professor of gynecology and obstetrics at Stanford's School of Medicine, explained the study, which involves 300 to 400 women across the country. "Along with standard chemotherapy people are receiving the normal P53 gene, which is put into a virus -- like a common cold virus -- and injected into the patient's abdomen, where the cancer is. The virus infects the cancer cells, much as it would a normal cell, placing this normal DNA into the cell. There it starts producing the tumor-suppressing chemical, which results in the cancer cell dying." Preliminary data from Phase One studies has shown increased survival of about 30 percent.
Two other studies involving vaccines are brand new. One vaccine is designed to attack the part of a cell that creates CA125 -- a marker chemical produced by cancer cells. Much like a typical vaccine, this new drug causes a patient's immune system to build up antibodies to a particular chemical -- in this case CA125 -- so that the immune system actually attacks the cell. The vaccine currently is used in individuals who've completed therapy and have no evidence of disease, a point where the tumor load is small enough to treat with this system of immunotherapy. (People in that situation presently have only about a 50 percent chance of five-year survival.)
The second vaccine study includes an inspired twist. After a patient has undergone surgery for ovarian cancer, the removed cells are used to create a vaccine specific to that patient. "The vaccine may address the CA125 system," said Roberts, "but it's possible there'll be other antigens to take advantage of on the surface of the cancer cells." Currently this "designer" vaccine is used as a second-line treatment, after a patient completes conventional therapy.
A related study seeks to identify additional markers for ovarian cancer. "The CA125 is a marker that's not very specific," said Roberts. "So we're working with a company that's looking at the genetic makeup of the cells and identifying proteins that are specific to the cancer. If we find a more specific marker, then we can have a more definitive blood test for ovarian cancer."
Several studies are also being conducted in-house, that is, not in conjunction with pharmaceutical and biotech companies. One such study is testing the sleep-inducing agent thalidomide as an anti-angiogenic factor (something that blocks the development of blood cells). Because cancer cells have to produce blood vessels in order to grow, it's believed that cutting off the production of new blood supply will extremely limit a cancer's ability to spread.
"We use thalidomide in conjunction with other chemotherapy in fairly high-risk patients who have had a number of therapies," said Roberts. "Normally you'd expect 10 or 15 percent of the people to respond to routine chemotherapy, and we've been able to double that with the thalidomide."
Also in-house is a program focused on a subtype of ovarian cancer called clear cell carcinoma. The variant, which makes up five to 10 percent of ovarian cancers, is highly malignant and responds poorly to standard therapy. A new regimen combines additional drugs with standard treatment. "Where patients might have survived only a year or so, we've got people surviving for a couple years," Roberts said.
An other project, combining drugs from standard first-line therapy with second-line drugs, has increased remission rates from 20 percent to 60 percent in other patients with other ovarian cancers, he said.
In the near future Roberts expects advances in genetics that will allow missing genes to be provided, defective cells to be corrected and new substances much like the angiogenic factors to be produced. "We're also getting drugs that are more active and provide a higher chance and longer duration of response, so in the near future ovarian cancer may be equated to something like arthritis or diabetes -- as a chronic but treatable illness."