- What are targeted cancer therapies?
Targeted cancer therapies are drugs or other substances that block the growth
and spread of cancer by interfering with specific molecules involved in tumor
growth and progression. Because scientists often call these molecules “molecular
targets,” targeted cancer therapies are sometimes called “molecularly
targeted drugs,” “molecularly targeted therapies,” or other
similar names. By focusing on molecular and cellular changes that are specific
to cancer, targeted cancer therapies may be more effective than other types
of treatment, including chemotherapy
and radiotherapy,
and less harmful to normal cells.
Many targeted cancer therapies have been approved by the U.S. Food and Drug
Administration (FDA) for the treatment of specific types of cancer (see details
in Questions 4 and 5). Others are being studied in clinical
trials (research studies with people), and many more are in preclinical
testing (research studies with animals).
Targeted cancer therapies are being studied for use alone, in combination
with other targeted therapies, and in combination with other cancer treatments,
such as chemotherapy.
- How do targeted cancer therapies work?
Targeted cancer therapies interfere with cancer cell division (proliferation)
and spread in different ways. Many of these therapies focus on proteins
that are involved in cell signaling pathways, which form a complex communication
system that governs basic cellular functions and activities, such as cell
division, cell movement, how a cell responds to specific external stimuli,
and even cell death. By blocking signals that tell cancer cells to grow and
divide uncontrollably, targeted cancer therapies can help stop cancer progression
and may induce cancer cell death through a process known as apoptosis.
Other targeted therapies can cause cancer cell death directly, by specifically
inducing apoptosis, or indirectly, by stimulating the immune system to recognize
and destroy cancer cells and/or by delivering toxic substances to them.
The development of targeted therapies, therefore, requires the identification
of good targets—that is, targets that are known to play a key role in
cancer cell growth and survival. (It is for this reason that targeted therapies
are often referred to as the product of “rational drug design.”)
For example, most cases of chronic
myeloid leukemia (CML) are caused by the formation of a gene
called BCR-ABL. This gene is formed when pieces of chromosome
9 and chromosome 22 break off and trade places. One of the changed chromosomes
resulting from this switch contains part of the ABL gene from chromosome 9
coupled, or fused, to part of the BCR gene from chromosome 22. The protein
normally produced by the ABL gene (Abl) is a signaling molecule that plays
an important role in controlling cell
proliferation and usually must interact with other signaling molecules
to be active. However, Abl signaling is always active in the protein (Bcr-Abl)
produced by the BCR-ABL
fusion gene. This activity promotes the continuous proliferation of CML
cells. Therefore, Bcr-Abl represents a good molecule to target.
- How are targeted therapies developed?
Once a target has been identified, a therapy must be developed. Most targeted
therapies are either small-molecule drugs or monoclonal
antibodies. Small-molecule drugs are typically able to diffuse
into cells and can act on targets that are found inside the cell. Most monoclonal
antibodies usually cannot penetrate the cell’s plasma
membrane and are directed against targets that are outside cells or on
the cell surface.
Candidates for small-molecule drugs are usually identified in studies known
as drug screens—laboratory
tests that look at the effects of thousands of test compounds
on a specific target, such as Bcr-Abl. The best candidates are then chemically
modified to produce numerous closely related versions, and these are tested
to identify the most effective and specific drugs.
Monoclonal antibodies, by contrast, are prepared first by immunizing animals
(typically mice) with purified target molecules. The immunized animals will
make many different types of antibodies
against the target. Next, spleen
cells, each of which makes only one type of antibody, are collected from the
immunized animals and fused with myeloma
cells. Cloning of these fusion cells results in cultures of cells that produce
large amounts of a single type of antibody, or a monoclonal antibody. These
antibodies are then tested to find the ones that react best with the target.
Before they can be used in humans, monoclonal antibodies are “humanized”
by replacing as much of the non-human portion of the molecule as possible
with human portions. This is done through genetic
engineering. Humanizing is necessary to prevent the human immune system from
recognizing the monoclonal antibody as “foreign” and destroying
it before it has a chance to interact with and inactivate its target molecule.
- What was the first target for targeted cancer therapy?
The first molecular target for targeted cancer therapy was the cellular receptor
for the female sex hormone
estrogen,
which many breast
cancers require for growth. When estrogen binds to the estrogen
receptor (ER) inside cells, the resulting hormone-receptor complex activates
the expression of specific genes, including genes involved in cell growth
and proliferation. Research has shown that interfering with estrogen’s
ability to stimulate the growth of breast cancer cells that have these receptors
(ER-positive breast cancer cells) is an effective treatment approach.
Several drugs that interfere with estrogen binding to the ER have been approved
by the FDA for the treatment of ER-positive breast cancer. Drugs called selective
estrogen receptor modulators (SERMs),
including tamoxifen
and toremifene (Fareston®), bind to the ER and prevent estrogen binding.
Another drug, fulvestrant
(Faslodex®), binds to the ER and promotes its destruction, thereby
reducing ER levels inside cells.
Another class of targeted drugs that interfere with estrogen’s ability
to promote the growth of ER-positive breast cancers is called aromatase
inhibitors (AIs). The enzyme
aromatase is necessary to produce estrogen in the body. Blocking the activity
of aromatase lowers estrogen levels and inhibits the growth of cancers that
need estrogen to grow. AIs are used mostly in women who have reached menopause
because the ovaries
of premenopausal
women can produce enough aromatase to override the inhibition. Three AIs have
been approved by the FDA for the treatment of ER-positive breast cancer: Anastrozole
(Arimidex®), exemestane
(Aromasin®), and letrozole
(Femara®).
- What are some other targeted therapies?
Targeted cancer therapies have been developed that interfere with a variety
of other cellular processes. FDA-approved targeted therapies are listed below:
- Some targeted therapies block specific enzymes and growth
factor receptors involved in cancer cell proliferation. These drugs are
also called signal
transduction inhibitors.
- Imatinib
mesylate (Gleevec®) is approved by the FDA to treat gastrointestinal
stromal tumor (a rare cancer of the gastrointestinal
tract) and certain kinds of leukemia.
It targets several members of a class of proteins called tyrosine kinase
enzymes that participate in signal transduction. These enzymes are overactive
in some cancers, leading to uncontrolled growth. It is a small-molecule
drug, which means that it can pass through cell membranes
and reach targets inside the cell.
- Dasatinib
(Sprycel®) is FDA approved to treat some patients with chronic
myeloid leukemia and acute
lymphoblastic leukemia. It is a small-molecule inhibitor of several
tyrosine kinase enzymes.
- Nilotinib
(Tasigna®) is FDA approved to treat some patients with CML. It
is another small-molecule tyrosine
kinase inhibitor.
- Trastuzumab
(Herceptin®) is FDA approved for the treatment of certain types
of breast cancer. It is a monoclonal antibody that binds to the human
epidermal growth factor receptor 2 (HER-2). HER-2, a receptor with
tyrosine kinase activity, is expressed at high levels in some breast cancers
and also some other types of cancer. The mechanism by which trastuzumab
acts is not completely understood, but one likely possibility is that
by binding to HER-2 on the surface of tumor cells that express high levels
of HER-2, it prevents HER-2 from sending growth-promoting signals. Trastuzumab
may have other effects as well, such as inducing the immune system to
attack cells that express high levels of HER-2.
- Gefitinib
(Iressa®) is approved by the FDA to treat patients with advanced
non-small
cell lung cancer. Its use is restricted to patients who, in the opinion
of their treating physician,
are currently benefiting, or have previously benefited, from gefitinib
treatment. This small-molecule drug inhibits the tyrosine kinase activity
of the epidermal growth
factor receptor (EGFR),
which is overproduced by many types of cancer cells.
- Erlotinib
(Tarceva®) is approved by the FDA to treat metastatic
non-small cell lung cancer and pancreatic
cancer that cannot be removed by surgery
or has metastasized. This small-molecule drug inhibits the tyrosine kinase
activity of EGFR.
- Cetuximab
(Erbitux®) is a monoclonal antibody that is FDA approved for treating
some patients with squamous
cell carcinoma of the head and neck or colorectal
cancer. It binds to the external portion of EGFR, thereby preventing
the receptor from being activated by growth signals, which may inhibit
signal transduction and lead to antiproliferative effects.
- Lapatinib
(Tykerb®) is FDA approved for the treatment of certain types of
advanced or metastatic breast cancer. This small-molecule drug inhibits
several tyrosine kinases, including the tyrosine kinase activity of HER-2.
Lapatinib
treatment prevents HER-2 signals from activating cell growth.
- Panitumumab
(Vectibix®) is FDA approved to treat some patients with metastatic
colon
cancer. This monoclonal antibody attaches to EGFR and prevents it
from sending growth signals.
- Temsirolimus
(Torisel®) is approved to treat patients with advanced renal
cell carcinoma. This small-molecule drug is a specific inhibitor of
a kinase called mTOR that is activated in tumor cells and stimulates their
growth and proliferation.
- Some targeted therapies induce cancer cells to undergo apoptosis
(cell death).
- Bortezomib
(Velcade®) is approved by the FDA to treat some patients with
multiple
myeloma. It is also approved for the treatment of some patients with
mantle
cell lymphoma. Bortezomib
causes cancer cells to die by interfering with the action of a large cellular
structure called the proteasome, which degrades proteins. Proteasomes
control the degradation of many proteins that regulate cell proliferation.
By blocking this process, bortezomib causes cancer cells to die. Normal
cells are affected, too, but to a lesser extent.
- Other targeted therapies block the growth of blood vessels
to tumors (angiogenesis).
To grow beyond a certain size, tumors must obtain a blood
supply to get the oxygen
and nutrients
needed for continued growth. Treatments that interfere with angiogenesis
may block tumor growth.
- Bevacizumab
(Avastin®) is a monoclonal antibody that is approved for the treatment
of glioblastoma.
It is also approved for some patients with non-small cell lung cancer,
metastatic breast cancer, and metastatic colorectal cancer. Bevacizumab
binds to the vascular endothelial growth factor (VEGF).
This prevents VEGF from interacting with its receptors on endothelial
cells, a step that is necessary for the initiation of new blood vessel
growth.
- Sorafenib
(Nexavar®) is a small-molecule inhibitor of tyrosine kinases that
is FDA approved for the treatment of advanced renal cell carcinoma and
some cases of hepatocellular
carcinoma. One of the kinases that sorafenib
inhibits is involved in the signaling
pathway that is initiated when VEGF binds to its receptors. As a result,
new blood vessel development is halted. Sorafenib also blocks an enzyme
that is involved in cell growth and division.
- Sunitinib
(Sutent®) is another small-molecule tyrosine kinase inhibitor
that is FDA approved for the treatment of patients with metastatic renal
cell carcinoma or gastrointestinal stromal tumor that is not responding
to imatinib.
It blocks kinases involved in VEGF signaling, thereby inhibiting angiogenesis
and cell proliferation.
- Some targeted therapies act by helping the immune system to
destroy cancer cells.
- Another class of targeted therapies includes monoclonal antibodies
that deliver toxic molecules to cancer cells specifically.
- Gemtuzumab
ozogamicin (Mylotarg®) is FDA approved to treat some patients
with acute
myeloid leukemia. It is a monoclonal antibody directed against the
protein CD33, which is found on the surface of leukemic blast
cells, linked to an antitumor
substance called calicheamicin. Gemtuzumab
ozogamicin is taken up by cells that express CD33 and, once inside,
the calicheamicin portion prevents DNA
synthesis.
- Tositumomab
and 131I-tositumomab (Bexxar®) is approved to treat certain types
of B-cell non-Hodgkin lymphoma. It is a mixture of monoclonal antibodies
that recognize the CD20 molecule. Some of the antibodies in the mixture
are linked to a radioactive
substance called iodine-131.
The 131I-tositumomab
component delivers radioactive energy to CD20-expressing B cells specifically,
reducing collateral damage to normal cells of the type that is seen with
traditional radiotherapy. In addition, the binding of tositumomab to the
CD20-expressing B cells triggers the immune system to destroy these cells.
- Ibritumomab
tiuxetan (Zevalin®) is FDA approved to treat some patients with
B-cell non-Hodgkin lymphoma. It is a monoclonal antibody directed against
CD20 that is linked to a molecule that can bind radioisotopes
such as indium-111 or yttrium-90.
The radiolabeled
forms of Zevalin
deliver a high dose
of radioactivity to cells that express CD20.
- Cancer vaccines
and gene
therapy are often considered to be targeted therapies because they interfere
with the growth of specific cancer cells. Information about these treatments
can be found in the following National Cancer Institute (NCI) fact sheets,
which are available on the Internet or by calling NCI’s Cancer
Information Service (CIS) (see below):
- What impact will targeted therapies have on cancer treatment?
Targeted cancer therapies give doctors a better way to tailor cancer treatment,
especially when a target is present in some but not all tumors of a particular
type, as is the case for HER-2. Eventually, treatments may be individualized
based on the unique set of molecular targets produced by the patient’s
tumor. Targeted cancer therapies also hold the promise of being more selective
for cancer cells than normal cells, thus harming fewer normal cells, reducing
side
effects, and improving quality
of life.
Nevertheless, targeted therapies have some limitations. Chief among these
is the potential for cells to develop resistance to them. In some patients
who have developed resistance to imatinib, for example, a mutation
in the BCR-ABL gene has arisen that changes the shape of the protein so that
it no longer binds this drug as well. In most cases, another targeted
therapy that could overcome this resistance is not available. It is for
this reason that targeted therapies may work best in combination, either with
other targeted therapies or with more traditional therapies.
- Where can I find information about clinical trials
of targeted therapies?
FDA-approved targeted cancer therapies continue to be studied in clinical
trials, as indicated by the list below. In the HTML version of this fact sheet
on NCI’s Web site (http://www.cancer.gov/cancertopics/factsheet/Therapy/targeted),
the drug names are links to search results for trials in NCI’s clinical
trials database. This database can also be searched on NCI’s Web site
by visiting http://www.cancer.gov/clinicaltrials/search
on the Internet. The database includes all NCI-funded clinical trials and
many other studies conducted by investigators at hospitals and medical centers
in the United States and other countries around the world.
Targeted Cancer Therapies Currently Being Studied in Clinical Trials:
Alemtuzumab
(Campath®)
Anastrozole
(Arimidex®)
Bevacizumab
(Avastin®)
Bortezomib
(Velcade®)
Cetuximab
(Erbitux®)
Dasatinib
(Sprycel®)
Erlotinib
Hydrochloride (Tarceva®)
Exemestane
(Aromasin®)
Fulvestrant
(Faslodex®)
Gefitinib
(Iressa®)
Gemtuzumab
Ozogamicin (Mylotarg®)
Ibritumomab
Tiuxetan (Zevalin®)
Imatinib
Mesylate (Gleevec®)
Lapatinib
Ditosylate (Tykerb®)
Letrozole
(Femara®)
Nilotinib
(Tasigna®)
Panitumumab
(Vectibix®)
Rituximab
(Rituxan®)
Sorafenib
Tosylate (Nexavar®)
Sunitinib
Malate (Sutent®)
Tamoxifen
Temsirolimus
(Torisel®)
Toremifene
(Fareston®)
Tositumomab
and 131I-tositumomab (Bexxar®)
Trastuzumab
(Herceptin®)
- What are some resources for more information?
NCI’s Molecular Targets Development Program (MTDP) is working to identify
and evaluate molecular targets that may be candidates for drug development.
As part of NCI’s Center for Cancer Research (CCR), the MTDP provides
research support for NCI-designated, high-priority drug discovery, development,
and research focused on specific molecular targets, pathways, or processes.
The MTDP’s Web site is located at http://home.ncifcrf.gov/mtdp/
on the Internet.
NCI’s Chemical Biology Consortium (CBC)
will focus efforts and resources on drug candidate identification and optimization
to enhance the entry of early-stage
drug candidates into the NCI therapeutics pipeline. The CBC is part of the
NCI’s Experimental
Therapeutics Program, which is a collaborative effort of CCR and NCI’s
Division of Cancer Treatment and Diagnosis.
More information about the CBC, which is being launched in August 2009, can
be found at http://dctd.cancer.gov/CurrentResearch/ChemicalBioConsortium.htm
on the Internet.
We offer comprehensive research-based information for patients and their families, health professionals, cancer researchers, advocates, and the public.
