January 1, 2008

Coming Soon? Targeted Therapies for Ovarian Cancer

Frederick Sweet, Ph.D.
Frederick Sweet, Ph.D. is Professor of Reproductive Biology in Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, Missouri.

It is a grim truth that, on average, one out of every fifty American women will develop ovarian cancer. Even though incremental chemotherapy advances have helped more women to survive ovarian cancer in the past few decades, the majority of those diagnosed with this disease will still die of it. One reason for this is that there is no practical test to diagnose ovarian cancer in its early stages. As with most cancers, chemotherapy and other treatments work much better when the disease is in its early stages. Most cases of ovarian cancer are not diagnosed until the disease has spread beyond the ovaries and into other parts of the body, at which point a woman's chances for survival are very low.

Lately, promising research has been done in the area of so-called "targeted therapy," which has raised hopes that far more effective treatments for ovarian cancer may be available soon.

Most cases of ovarian cancer are not diagnosed until the disease has spread beyond the ovaries and into other parts of the body, at which point a woman's chances for survival are very low.

The basic concept of targeting therapies against infections has been around for more than a century. We take for granted the many effective targeted therapies against bacteria, which appear on pharmacy shelves worldwide under the name antibiotics. Hopefully, someday we will see equally effective, targeted anticancer drugs on those same shelves.

Targeted Therapy
The magic bullet concept originated with a 19th-century scientist who proposed that if a compound could be made that selectively targeted a disease-causing organism, then a toxin for killing that organism could be delivered by linking it to the chemical agent that selects the tissue. The goal was to create a drug that could attack a parasitic or hostile invader without harming the host (i.e., us). The first successful magic bullet was Salvarsan (or arsphenamine), which remained the only cure for syphilis until it was replaced after World War II by penicillin and other antibiotics.

Using the Immune System
Ever since, scientists have searched for a a way to direct an anticancer drug to its target while bypassing normal tissues would be developed using the body's own immune system. The reason for this is that the immune system, by its nature, serves as an open expressway within the body. It has easy access to all tissues, as well as sophisticated ways of detecting and identifying unhealthy agents and substances. The immune system fights infection by identifying proteins belonging to invading foreign bodies (antigens) and using these as a sort of target, marking them for destruction. It then creates antibodies that zero in on these antigens and destroy them. Using the immune system to deliver anticancer agents requires the discovery of a unique cell surface protein from the targeted cancer. This unique protein would serve as an antigen from which to produce the complementary antibody, which would act as a "transport agent," delivering the therapy directly to the cancer.

Using the immune system to deliver anticancer agents requires the discovery of a unique cell surface protein from the targeted cancer.

Today, scientists are working on using various antibodies as just such a "transport agent."3 They are working on overcoming two main difficulties with using an antibody to deliver targeted therapy. One is that to be therapeutic requires using very large amounts of the antibody, which are not easy to acquire. Second, new chemical methods have had to be devised for linking an anticancer agent to the antibody. A common practical obstacle to targeted cancer therapies is that the chemical changes needed to link them to an antibody often reduce their strength.4 It appears that it may take a great deal of experimentation to find the best configuration before an antibody-drug complex will be able to be used for targeted therapy.

Targeted Radiation Therapy
Another form of targeted therapy that is currently under study is the idea of using antibodies to deliver small amounts of radiation to cancerous cells within the body. This has obvious advantages over conventional radiation therapy, which exposes large amounts of healthy tissue to radiation, which can be dangerous. In a recent experiment, a radioisotope (an atom that emits radiation) was combined with an antibody and given to 20 ovarian cancer patients, along with the anticancer drug paclitaxel. Participants ranged in age from 39 to 77 years. The results suggested that combining chemotherapy with targeted radiation therapy via the immune system worked better than the chemotherapy alone.

Using Anti-Coagulants for Cancer
Scientists have long known that there is a connection between the mechanisms in the blood that cause and regulate coagulation, or clotting, and tumor cell growth and metastasis (the spreading of cancer to other tissues throughout the body).11 For this reason, researchers have focused on coagulation as a possible source of new ways to treat ovarian cancer. Recent studies suggest that disrupting parts of the coagulation process may lead to a useful cancer therapy.

For example, heparin is the most extensively used anticoagulant drug. Among other things, it is used for treating deep vein thrombosis, a condition in which a blood clot forms in the leg; if it travels to the lungs, it can cause a life-threatening pulmonary embolism. Studies of deep vein thrombosis treatment have shown that cancer patients with thrombosis who are being treated with heparin have better survival rates than among those treated without heparin. This suggests the possibility that anticoagulant drugs could inhibit the growth of ovarian and other cancers.

A recent experiment studied a combination of chemotherapy and anticoagulant drugs used to treat lung cancer patients. The results suggested that anticoagulants could slow down the progress of cancer.

Another study compared a group of cancer patients given a placebo with a group given the anticoagulant heparin. The cancers in the study included breast, colorectal, ovarian and pancreatic. Thirty-four percent (34%) of the heparin group and 31% of the placebo group received chemotherapy alone, 8% of each group received radiation therapy alone; the remainder received radiation and chemotherapy. Estimated overall survival at one, two and three years was not significantly different between the groups. But the estimated overall survival among those with less-advanced cancer when they enrolled in the study was significantly longer in the heparin group, both at two years and at three years.

A second study confirmed these findings. Although the exact mechanism by which heparin helps fight cancer development and metastasis is not yet known, further research is being done on the drug as a potential targeted therapy.

Targeted Gene Therapy
There is widespread optimism about gene therapy as an important treatment for cancer. Experts think that ovarian cancer is caused by a build-up of genetic defects or "mistakes" within cells. These genetic defects may be inherited or they may be caused by exposures to environmental factors such as poisons or pollution. The hope is that someday it may be possible to correct this kind of damage by transplanting normal genes into genetically damaged cells. Another idea is to alter tumor cells so that they attack themselves, become targeted by the immune system or become more vulnerable to chemotherapy. The strategies for gene-targeted therapy are somewhat similar to those developed for immunotherapy except, instead of antibodies doing the carrying and targeting, in gene therapy viruses would perform that function. Targeted gene therapy would be based on using a type of virus to selectively deliver a toxin that would attack only cancer cells.

What Is Taking So Long?
Despite some spectacular laboratory results, progress has been slow towards developing viable ovarian cancer-targeted gene therapy. One big technical roadblock is the difficulty of gathering enough information to perform the therapy with precision. The answer to this problem may well lie in improved noninvasive imaging. Imaging technology is advancing rapidly and noninvasive imaging techniques are likely to become increasingly important in the development of more effective targeted gene therapies. As more and better "transport agents" are developed, many researchers believe that gene therapy will offer much improved treatments for women with ovarian cancer.

The effectiveness of most treatments now available for ovarian cancer — surgery, chemotherapy, radiotherapy — is limited by the fact that the disease is rarely detected in its early stages. A number of new treatments, however, are now under development. Hundreds of clinical trials have examined the safety, effectiveness and side effects of gene therapy and other, so-called "targeted" therapies. Although some early findings look promising, the practical applications of gene therapy are still being worked out. As we learn more about the genetics and biochemistry of ovarian cancer, the closer we are coming to developing genetic and other targeted therapies that will save women's lives.
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