• Introduction
• Gene therapy
• Monoclonal antibodies
• Vaccines and immunotherapy
• Anti-angiogenesis factors
• Other new targeted therapies in clinical trials

Since every cancer is composed of many different types of cells, each responding to different kinds of growth factors and other signals, the specifically targeted cancer treatments of the future are likely to be complex mixtures of chemicals, individually tailored to each individual tumor a far cry from today's less specific chemotherapies that have an impact on all rapidly dividing cells in the body. While these newer substances don't usually kill all cancer cells, they produce their therapeutic results with minimal side effects, potentially turning the cancer into a manageable, chronic illness that may be prevented from progressing.

Gene therapy

More than half of all cancer patients (and probably a third of breast cancer patients) share a mutation in the p53 gene, which suppresses tumor growth. "Often called the guardian of the genome," according to researchers Oliff, Gibbs and McCormick, "it prevents replication of damaged DNA in normal cells and promotes suicide, or apoptosis, of cells with abnormal DNA."³ Researchers are working on creating viruses carrying healthy tumor-suppresser genes, that can actually "infect" cancer cells. Using the adenovirus that causes the common cold, they inactivate the cold virus by deleting the gene causing its replication process, and slipping the p53 gene into its place. Early human testing has shown some ability to stop tumor growth and even cause some tumors to decrease in although there have been problems delivering the virus to all areas of tumor.

Tests have begun on another such gene, known as E1A, in women with cancer of the breast or ovaries. Stem cells infused with the MDR (multi-drug-resistant) gene are being used in conjunction with high-dose chemotherapy in an attempt to circumvent the drug resistance that makes most such procedures fail.

Another genetic therapy in early stages of clinical trials is based on a growth-signaling oncogene known to researchers as RAS, present in about 30 percent of breast cancers and even more common in pancreatic, colon and lung cancers. This gene, when active, tells cells to divide repeatedly. A number of drug companies are currently working on RAS inhibitors, which some investigators feel may show even more promise than the anti-HER-2/neu drugs discussed in the next section.

Monoclonal antibodies

Herceptin (anti-HER-2/neu humanized monoclonal antibody) is likely to be the first of the new gene-based therapies for use in breast cancer to make it to the market. Herceptin targets the HER-2/neu protein, produced in excess amounts in some women with breast cancer. Over-expressors of this substance, about 30 percent of women with breast cancer, have too many copies of the HER-2/neu oncogene, which makes a protein that helps send the signal for cells to divide. In clinical trials with heavily pre-treated metastatic breast cancer patients, both as a single agent and more effectively in combination with Adriamycin or Taxol, Herceptin has shown some effectiveness against this particular breast cancer cell mutation, which tends to be aggressive, hard to treat, and resistant to hormonal manipulation. When it works, as it seems to with a significant minority of over-expressors, it has prolonged the time to tumor progression by a few months to several years. Its side effects have been relatively mild, with flu-like symptoms in the early treatments, and some reversible cardiotoxicity in combination with Adriamycin and Taxol. At the time of this writing, this drug is expected to become available as early as late 1998. In the next years, HER-2/neu testing may become a routine part of the staging process for newly diagnosed breast cancer patients, and Herceptin may well have a role to play in adjuvant treatment.

Other antibodies in development target other growth factors. Antibodies for EGF (epidermal growth factor) are currently being tested in head and neck cancers, and a drug known as SU101 which targets PDGF (platelet-derived growth factor) has shown good response in glioblastoma, a particularly deadlybrain cancer.

Vaccines and immunotherapy

Since cancer has the ability to evade the body's own immune system, augmenting immune response is another possible approach. Biological response modifiers like Interleukin-2 have been used to stimulate the immune system. Because patients receiving allogenic (donor) transplants following high-dose chemotherapy often seem to do better despite graft-versus-host-disease (a frequent and troublesome side-effect of donor transplants) a few researchers are now experimenting with inducing low-grade GVHD in people who've undergone autologous stem cell transplants, reasoning that an immune system stimulated by GVHD might be more likely to search out and destroy cancer cells as well.

Trying to induce an immune response specific to cancer is painstaking, complex, and frustrating work. Lloyd Old, an immunology researcher at Memorial Sloane-Kettering Cancer Center, puts the task into perspective:

Despite the great hope of immunotherapy, a dark cloud hangs over all our attempts to control cancer by immune mechanisms. Cancer cells are masters of deceit and veritable Houdinis that can readily alter themselves to evade immunologic recognition and attack.

Perhaps these therapies will yield the universal objective of cancer researchers, health care providers and, of course, patients. A more achievable aim, though, may be developing therapies that can change the nature of cancer from a progressive and lethal disease to one that can be controlled throughout a long life. That result would be less than ideal, but it could make a world of difference for many afflicted with tumors not readily treatable today.⁵

Anti-angiogenesis factors

Once neovascularization occurs, hundreds of new capillaries converge on the tiny tumor; each vessel soon has a thick coat of rapidly dividing tumor cells. Some of these cells are not angiogenic but are nonetheless sustained by capillaries recruited by neighboring cells. Now the tumor can expand in a matter of months, the mass may reach one cubic centimeter in size and contain around one billion tumor cells.⁶

Antiangiogenic therapy, in contrast to many other therapeutic approaches, does not aim to destroy tumors. Instead, by limiting their blood supply, it attempts to shrink tumors and prevent them from growing. Antiangiogenic drugs stop new vessels from forming around a tumor and break up the existing network of abnormal capillaries that feeds the cancerous mass.

Other new targeted therapies in clinical trials

Retinoids like 4HPR, which are derivatives of Vitamin A, can induce a process called apoptosis, or programmed cell death, in cancer cells. Some retinoids have actually been able to induce a reversal of the process by which cancer cells become undifferentiated, or less like normal cells. This differentiation therapy has proved effective in some kinds of leukemia, and is beginning to be used in solid tumors. A new retinoid known as Targretin (bexarotene), already in trials for lymphoma, lung and other cancers, has demonstrated tumor regression in Tamoxifen-resistant tumors in animals and will soon be in clinical trials with advanced breast cancer patients.

Since cancer clearly involves something gone wrong in the normal genetic controls over cellular processes, such as growth, it's a good bet that many of the keys to future successful treatments will be found through genetic research. On the Internet, the NCI CancerNet Service offers a good place to look for experimental treatments currently in clinical trials, as does the Centerwatch Clinical Trials Listing Service. Both web sites explain the nature of clinical trials.⁷

Many of the people interviewed for this book found out about new forms of treatment from other patients participating in the Breast Cancer Listserv on the Internet. Online discussion groups are often an excellent place to find out information concerning treatments not yet widely known in the oncology community. Although they don't have an oncologist's expertise, of course, well-informed patients who keep up with the medical literature will often find out about new drugs, or new uses and combinations of older drugs, before their oncologists do.

Notes

1. Allen Oliff, Jackson B. Gibbs, and Frank McCormick, "New Molecular Targets for Cancer Therapy," Scientific American (September 1996).
2. Daniel A. Haber, and Eric R. Fearon, "The Promise of Cancer Genetics," Lancet 351, no. 2 (1998): 1-8.
3. Oliff, "New Molecular Targets for Cancer Therapy."
4. Robert S. Boyd, "Sharpening the Attack on Cancer," The Philadelphia Enquirer, 9 May 1998.
5. Lloyd J. Olds, "Immunotherapy for Cancer," Scientific American (September 1996).
6. Judah Folkman, "Fighting Cancer by Attacking Its Blood Supply," Scientific American (September 1996).
7. NCI CancerNet Clinical Trials information is at http://wwwicic.nci.nih.gov/trials/h_clinic.htm and Centerwatch Clinical Trials Listing Service is at http://www.centerwatch.com/.