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The New Targeted Biological Therapies


The following article is excerpted from Chapter Six of Advanced Breast Cancer: A Guide to Living with Metastatic Disease, 2nd Edition by Musa Mayer, copyright 1998, published by O'Reilly & Associates, Inc. For book orders/information, call 1-800-998-9938. Permission is granted to print and distribute this excerpt for noncommercial use as long as the above source is included. The information in this article is meant to educate and should not be used as an alternative for professional medical care.

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

In cancerous tumors, genes that normally keep cell growth in check become damaged and no longer are able to function. Over fifty of these mutated genes have been identified in a variety of cancers, and these fall for the most part into three major classes: oncogenes, tumor suppresser genes and mutated reparative genes. Oncogenes control cell growth, and are mutant versions of normal genes. According to pharmaceutical researchers Allen Oliff, Jackson B. Gibbs and Frank McCormick, an oncogene "stimulates cell progression through the cell the sequence of events in which a cell gets larger, replicates its DNA and divides, passing a complete set of genes to each daughter cell."1 Tumor suppressor genes normally prevent the growth of malignancies, acting as a kind of brake on cell growth and progression. "Many cancers result from the loss or malfunction of the key regulatory proteins that these genes encode," state Oliff, Gibbs and McCormick. The third type of cancer-related gene, mutated reparative genes, governs the repair and replication of DNA. Without these reparatory mechanisms, the researchers write, "the chances that a damaged gene will be repaired fall drastically, and the likelihood rises that the damage will ultimately be transmitted to the cell's progeny as a permanent mutation." The first two types of genes have diverse functions in growth regulation, differentiation and programmed cell death. Mutated reparative genes have a more indirect role in cancer growth, according to an article on cancer genetics in Lancet: "These genes are involved in DNA repair and in maintaining the integrity of the genome in the face of DNA-damaging agents, such as ionizing radiation."2

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

Researchers have found that growth factors and their receptors play a key regulatory role in cell proliferation and oncogenesis. Monoclonal antibodies target certain proteins on the surface or on the nucleus of the cancer cells to block certain key sites, interfering with a tumor's ability to absorb the growth factors it needs from the bloodstream.

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

Cancers are extremely clever at evading the body's immune defenses. Researchers experimenting with dozens of "personalized" vaccines made from antigens taken from a patient's own tumor cells are trying to provoke an immune response whereby the patient's white blood cells would be induced to attack the cancer. Trials with melanoma patients have already shown favorable results with this relatively non-toxic approach. "We plan to kick-start the immune system," says Dr. Brian Czerniecki, of the University of Pennsylvania's School of Medicine.4 There and at Stanford, vaccines are being made from rare, star-shaped "dentritic" white blood cells, which alert the immune system to the presence of cancer. The potential problem with this approach stems from the fact that tumor cells have many different kinds of mutations, each of which would have to be identified and targeted. Currently in clinical trials is a vaccine against breast cancer polypeptide MUC-1 linked with agents that stimulate the immune system. Vaccines against RAS and p53 oncogenes are also being tested, and an antibody-linked vaccine called TriAb has shown immune activity in heavily pre-treated metastatic breast cancer patients against the HMFG antigen, present in the breast cancer cells.

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

To grow beyond the size of a small pea, all solid tumors require their own blood supply to deliver nutrients. Tumors thus have to force the construction of special blood vessels. To accomplish this, they secrete substances that stimulate blood vessel growth in neighboring tissue, inducing the nearest blood vessels to grow new branches in their direction, a process known as angiogenesis. Judah Folkman, whose research group at Children's Hospital Medical Center of Harvard Medical School has been researching angiogenesis since the 1970s, describes what happens then:

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
In 1992, clinical testing began with the first anti-angiogenic drug, known as TNP-470. Dozens of substances are currently being tested that block angiogenesis, although some chemicals identified as anti-angiogenic, like interferon, have proved too weak to produce significant effects in highly malignant tumors. These drugs work in a radically different way than other cancer therapies, Folkman emphasizes:

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.
Prior to the 1998 conference of the American Society of Clinical Oncology, Folkman and his research group received enormous but premature media attention for dramatic results in experiments in mice. He hopes to have his drugs, endostatin and angiostatin, in human trials within a year or two. Among the nine antiangiogenic substances currently being tested in clinical trials with breast cancer patients are Marimastat, SU5416, Neovastat, Combretastatin, squalamine, TNP-470, and the same drug whose antiangiogenic capacity produced birth defects when it was used during pregnancy. One company is working on development of a "tumor homing peptide" that links to the anti-cancer drug doxorubicin in a compound called THP-dox, the company finds and destroys developing blood vessels in tumors.

Other new targeted therapies in clinical trials

Anti-metastatic factors are directed at enzymes that help cancer cells enter the bloodstream, dissolve tissue and move through capillary walls. An enzyme called telomerase, necessary to cancer cells so that they can keep on dividing, has been isolated, and researchers are working on telomerase-blockers that will force cancer cells to age and die like normal cells. So-called "antisense" molecules have been developed to replace strings of DNA that tell oncogenes to produce growth-promoting proteins.

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/.

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