Targeted Therapies Take Aim at Cancer
All anticancer drugs target tumors in some way. Most conventional treatments, however,
attack healthy cells as well as cancer cells. As a result, there can be serious side
effects from the treatment. A new approach to cancer treatment may help reduce side
effects. The new treatment is called targeted therapy. It takes a more direct aim
at cancer cells. And that can means less damage to healthy cells.
Targeted therapies are designed to recognize a specific molecular change in a cancer
cell that drives the growth and spread of a tumor. By zeroing in on its molecular
target, these new medications destroy or slow the growth of cancer cells while avoiding
normal, healthy cells. And because healthy tissues are spared, targeted therapies
tend to bring about fewer and less severe side effects than conventional treatments.
How knowing the problem can lead to the treatment
Trillions of cells make up the normal, healthy body. Cells grow and divide in a controlled
manner according to a complex system of chemical signals within the cells. These signaling
pathways tell cells when to divide, when to be at rest, and even when to die. Such
signals help each tissue and organ in the body maintain its proper shape and function.
If a problem arises in a cell's signaling system, it can push a healthy cell toward
becoming a cancerous one. Usually, more than one signal has to go haywire for a tumor
to arise. But over time, if a number of critical molecular changes accumulate, the
healthy cell is transformed into a cancer cell.
Scientists have identified many molecular mistakes that lead to cancer. Defects in
genes are a very common molecular change seen in cancer. Genes are stretches of DNA
located within cells. The role of genes is to provide cells with instructions for
producing proteins. Damaged genes make flawed proteins. Many proteins are involved
in signaling. So, flawed proteins disrupt the signaling pathways that are essential
for a cell to function normally.
Identifying the exact mistakes that lead to cancer can help doctors and researchers
know how to treat cancer. Once a critical flaw has been identified, researchers search
for a medication that can interfere with an abnormal molecule or malfunctioning process.
The drug's interference in the malfunctioning process can inhibit the cancer's progression
or even eliminate the tumor.
Types of targeted therapy
Some targeted therapies home in on tumors by seeking out molecules found only in cancer
cells. Other targeted agents seek out molecules that are more abundant in cancer cells
than in healthy cells. And still other treatments are focused on processes that are
more important to the growth of cancer cells than normal cells.
There are two main classes of molecularly targeted agents under development: small
molecule compounds and monoclonal antibodies.
Small molecule compounds
Small molecule compounds are medications that interfere with the molecular machinery
of cancer cells that can cause them to die or stop their growth. Many of these drugs
can be taken by mouth.
One example of a small molecule compound is Gleevec (imatinib). It's used to treat
a rare stomach cancer called gastrointestinal stromal tumor (GIST) and certain types
Chronic myelogenous leukemia (CML) is an unusual type of cancer in that only one molecular
defect is needed to turn a normal cell into a cancerous one. The abnormality arises
when two genes fuse together and, as a result, produce an abnormal protein. This protein
sends a signal to the cell that tells it to grow in an uncontrolled manner. Gleevec
controls the growth of CML tumors by preventing the abnormal protein from signaling
the cancer cells to grow.
Gleevec is also effective against other tumors that have defects in proteins similar
to the one involved in CML.
Many other small molecularly targeted therapies are being created. Tarceva (erlotinib)
was approved by the U.S. Food and Drug Administration (FDA) to treat metastatic non-small
cell lung cancer and pancreatic cancer in certain circumstances or tumor types. Tarceva
works by inhibiting a protein called the epidermal growth factor receptor (EGFR) from
signaling the cell to grow. For this reason, it is classified as an EGFR inhibitor.
EGFR is produced in excessive amounts by many tumors, such as those found in lung,
breast, head and neck, pancreas, and colon cancer. However, tumors that have certain
mutations in EGFR are most effectively treated with the drug erlotinib. In advanced
stage lung cancer for example, EGFR mutated lung cancer is more effectively treated
with erlotinib than with standard (nontargeted) chemotherapy. Whether a lung cancer
has this EGFR mutation can be determined by a special molecular test performed on
the patient’s tumor (biopsy). Because additional molecular defects give rise to these
cancers, more than just one drug will likely be needed to effectively control or destroy
The second category of targeted therapies is monoclonal antibodies. Antibodies are
normal components of the immune system that help rid the body of foreign invaders
or infectious agents such as bacteria. Antibodies recognize abnormal surface patterns
or antigens on the invader.
Antibodies trigger the body's immune response to an invader, and they are programmed
to remember previous invaders so that they can effectively and quickly destroy them
if they attack the body again.
Monoclonal antibodies are produced in a lab. They work in a similar way to the body's
natural antibodies. They locate and bind to antigens found on cancer cells and eliminate
them from the body. Monoclonal antibodies can be used alone to stimulate an immune
response, or they can be used to deliver drugs, toxins, or radioactive material directly
to a tumor.
Here are a few FDA-approved monoclonal antibody therapies:
Avastin (bevacizumab) has been approved by the FDA as first-line treatment for metastatic
colorectal cancer, meaning the cancer has spread, as well as in the treatment of some
other tumors including certain lung cancers, brain, and kidney cancers. It is the
first drug to be approved that works by targeting angiogenesis, which is the formation
of new blood vessels to the tumor.
Zevalin (ibritumomab tiuxetan) binds to the same CD20 target that Rituxan does, so
it's used to treat the same types of cancer as Rituxan. But Zevalin carries an additional
punch because its monoclonal antibody is bound to a radioactive compound called yttrium-90,
which can kill cancer cells. By delivering this damaging compound directly to the
tumor, Zevalin allows larger and more deadly doses of the radioactive agent to reach
the tumor while minimizing its damage to healthy cells.
Azerra (ofatumumab) is used for the treatment of chronic lymphocytic leukemia and
is directed against the CD20 cell surface antigen.
Yervoy (ipilimumab) is used to treat people with advanced melanoma. It is directed
against a T-lymphocyte-associated antigen-4 (CTLA-4), located on the surface of activated
Realizing a vision
In time, researchers envision being able to individualize cancer treatment for each
person. By testing a person's tumor cells to determine the exact molecular abnormalities
that are involved, the doctor would choose a combination of therapies to take specific
aim at the major defects in the cells of the tumor.
Before this scenario is realized, existing targeted therapies must be refined, new
targets and therapies must be identified, and the right combinations of agents must
be devised. While science is only at the beginning of this revolutionary approach
to cancer treatment, researchers are working toward making this vision a reality.