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