Conquering

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this issue
INSIDE
Conquering Cancer
with Drugs from
Nature’s Medicine
Cabinet
A life-saving compound from nature
1
Developing Taxol
2
Overcoming nature’s scarcity
3
Too toxic for therapy
4
Antibody-targeted therapies
7
Rapamycin: it’s complicated
8
Into the deep
8
Nature’s designs: tried and still true
10
Acknowledgments
Conquering Cancer with Drugs
from Nature’s Medicine Cabinet
Author, Cathryn M. Delude
Scientific Advisor, John A. Beutler, PhD, National Cancer
Institute, National Institutes of Health
Scientific Reviewer, David Newman, DPhil, National Cancer
Institute, National Institutes of Health
Breakthroughs in Bioscience committee
James E. Barrett, PhD, Chair, Drexel University College of
Medicine
Aditi Bhargava, PhD, University of California San Francisco
David Brautigan, PhD, University of Virginia School of Medicine
Rao L. Divi, PhD, National Cancer Institute, National Institutes
of Health
Marnie Halpern, PhD, Carnegie Institution of Washington
Tony E. Hugli, PhD, Torrey Pines Institute for Molecular Studies
Edward R. B. McCabe, MD, PhD, University of California Los
Angeles
Loraine Oman-Ganes, MD, FRCP(C), CCMG, FACMG, RBC
Life Insurance Company
Sharma S. Prabhakar, MD, MBA, FACP, Texas Tech University
Health Sciences Center
R. Brooks Robey, MD, FASN, FAHA, White River Junction VA
Medical Center and Geisel School of Medicine at Dartmouth
Paula Stern, PhD, Northwestern University Feinberg School of
Medicine
Breakthroughs in Bioscience Production
staFF
Managing Editor, Tyrone C. Spady, PhD, Legislative Affairs
Officer, FASEB Office of Public Affairs
Production Staff, Lawrence Green, Communications Specialist,
FASEB Office of Public Affairs
CovEr: Many of our most potent anti-cancer therapies
were discovered in or inspired by organisms that inhabit the
seas, forests, and other habitats. It was not until the 1940s
and after seeing the successful treatment of infectious
diseases that scientists began to examine the potential of
natural products to treat cancers. With new approaches to
identifying anticancer compounds and new technologies for
investigating the interaction of drug molecules with cancer
cells, researchers supported by the National Institutes
of Health and other agencies are bringing new drugs to
the medicine cabinets of patients in need. Images credits:
Darrin Klimek and Manuel Velasco.
Cancer
Therapies
Conquering Cancer
with Drugs
from Nature’s Medicine Cabinet
from nature
Despite a four decade “war on
cancer,” this year, 1.5 million
Americans will be diagnosed
with a form of this broad group
of diseases, and a half million will
die as a result. Until the early
part of the 20th Century, the standard way to treat cancer involved
cutting it out, sometimes crudely.
Radiation therapy, introduced in
1913, proved an effective way to
treat some cancers without surgery, but it also caused tremendous collateral damage to healthy
tissues. Beginning in the late
1930’s - early 1940’s, researchers were inspired by the success
in treating infectious diseases
with chemicals isolated from
microorganisms and other natural
products, such as penicillin from
a fungus. Could chemicals battle
cancer too? The first of such
drugs, a variant of mustard gas,
actually came from the battlefield
and owes its origin, ironically, to
the gas warfare conducted during
World War I. Early on, military
physicians realized that servicemen exposed to mustard gas had
diminished numbers of a type of
white blood cell known as a lymphocyte. Scientists then deduced
that this class of compounds
might be useful in the treatment
of cancer of the lymphocytes —
lymphoma— and other blood diseases. But the treatment was too
Breakthroughs in Bioscience
harsh and eventually fell from
use. Despite this initial failure
due to adverse side effects, the
discovery that chemicals could be
used to treat cancer was a watershed moment and foreshadowed
the century of medical breakthroughs that was to come.
A life-saving compound
from nature
Various folk remedies had
attributed anticancer properties to plants, but virtually no
scientific research had explored
the use of natural compounds,
from plant and other sources,
to treat cancers. Then in the
1950s, researchers discovered
that the Madagascar periwinkle
(Catharanthus genus) contained
biologically active compounds
called alkaloids. Periwinkle
alkaloids interfere with cell division in cancer cells, and so these
compounds became the basis for
a class of “vinca alkaloid” drugs,
which includes vincristine and
vinblastine, which are still in use
today.
In 1960, the National Cancer
Institute (NCI) began systematically screening other plants
for similar anticancer properties. NCI-funded researchers
collected a wide assortment of
samples—bark, leaves, stems,
1
Figure 1 — Madagascar periwinkle. The
Madagascar periwinkle (Catharanthus
roseus), also called Vinca, produced
some of the earliest drugs derived from
natural products. These Vinca alkaloids
include vinblastine and vincristine,
which are still in use today. Source:
Lorenzarius via Wikipedia.
seeds, roots—and tested extracts
from them for anticancer activity.
Extracts that either killed cancer
cells or slowed the growth of
tumors were sent to research laboratories for activity-guided fractionation, a process that isolates a
pure compound for further study.
Early in the process, the NCI
plant program teamed up with
the United States Department of
Agriculture (USDA) for more
widespread sample collection.
On a hot day in August 1962,
one of the USDA’s botanists,
Arthur Barclay, gathered specimens from a scraggly, slowgrowing Pacific yew tree, Taxus
brevifolia. This tree lives along
stream banks, gorges, and ravines
in old growth forests in the
Pacific Northwest. Because it is
poisonous, the yew has no natural
pests, and laboratory tests quickly
showed that an extract prepared
from it killed cancer cells. It
would take years to determine
what the anticancer compound
was and how it worked. Finally,
30 years later in 1992, the breakthrough drug derived from the
Pacific yew, Taxol, received Food
and Drug Administration (FDA)
approval for advanced ovarian
cancer. It has since saved untold
lives and extended others by many
New compounds are isolated
and purified from natural
sources or synthesized
The physiological, cellular, and/or genetic basis of a disease
is studied to identify potential therapeutic targets
In vitro (cell-based) laboratory
assays are developed to
measure the effect of
potential therapeutics
Before moving to testing in
humans, an Investigational
New Drug Application must
be filed with the FDA
PhAse I clinical
trials consist of drug
safety studies in
healthy humans
New Drug Development. Drug
discovery is an iterative process. It goes
back and forth between theoretical
biology; the necessary, appropriate,
and humane use of animal assays to
Breakthroughs in Bioscience
determine a compound’s biological
activity in the body; and medicinal
chemistry to optimize the compound.
Then in human studies, clinical
observations test hypotheses about
2
Lead compounds are
tested in vivo for safety
and efficacy, in laboratory
animals such as mice
and rats
PhAse II clinical
trials test whether
a drug works in a
small number of
patients affected
by the disease
how a candidate drug may target
cancer cells; determine its safety
and effective doses; and compare
its ability to shrink tumors or stop
cancer progression relative to standard
years. With metastatic ovarian
cancer, for example, the pendulum swung dramatically from 20
to 80 percent survival after five
years.
To illustrate the significance
of this breakthrough in cancer
therapy, consider the case of
Tia McAlpine. A 36-year-old
mother of three children, Tia
was diagnosed with advanced
ovarian cancer in May 1982.
Ovarian cancer is almost always
undetected until the tumor has
metastasized. Its presentation
Drug Development process
Using the in vitro laboratory
assay, 5,000-10,000 new
and previously developed
compounds are tested for
biological activity
On average, 250 of the compounds
tested possess the desired activity
and are now designated as “hits”
A handful of the most
promising hits are chosen
for chemical modification
to improve target specificity,
potency, chemical and
metabolic stability, water
solubility, and other
pharmacological parameters.
Improved hits are now known
as “lead compounds”
A New Drug
Application
is filed with
the FDA
PhAse III clinical
trials test large
numbers of patients
therapy. The NIh generally helps fund
all stages of research up through phase
II clinical trials, as indicated by the red
borders of some panels of the flowchart.
While NIh also supports some phase
Breakthroughs in Bioscience
III clinical trials, this portion of the
drug development process is usually
funded by industry and other private
organizations and is distinguished by
blue borders. Because this process is
3
so rigorous, only four to seven percent
of candidate drugs receive approval
from the Food and Drug Administration
(fDA).
then mimics other diseases and is
harder to treat. Tia began taking
a combination of cisplatin and
cytoxan, a debilitating regimen
that sapped the strength of this
formerly vigorous young woman.
The tumors did shrink, but by
Thanksgiving she relapsed.
She began another therapy that
held the cancer at bay for a few
months, and again relapsed. She
declined the only remaining
option: vincristine, a harsh
treatment that offered ovarian
cancer patients only a two
percent chance of a response.
“She had had enough,” explained
her husband Jim, a natural
product chemist. Tia died two
months later, thirteen months
after diagnosis—and just months
before the first trials for Taxol
began.
Fifteen years later in 1998,
Jim’s 46-year old sister Jan Ely
was also diagnosed with ovarian
cancer. She began Taxol immediately, went into remission, and
resumed her normal life with
her family. After six years she
relapsed and died two years later.
“Those eight years would have
made a big difference for Tia and
us, especially for our daughter
who was ten when her mother
died,” says Jim. “We tend not to
realize how much progress we
have made since Tia died.”
Developing Taxol
It took 30 years of research to
make Taxol available to people
like Tia. (To view a general
overview of how drugs are developed, see the flowchart “Drug
Development Process”) After
NCI confirmed the anticancer
Breakthroughs in Bioscience
properties of the yew sample,
scientists at Research Triangle
Institute in North Carolina
received 30 pounds of Taxus
yew bark in 1964. The researchers isolated a biologically active
compound that appeared to have
the chemical properties of an
alcohol. It was thus named Taxol,
Cancer is more than
the mere presence
of malignant cells. It
develops because cancer
cells are able to change
how someone’s nervous,
immune, and endocrine
systems interact with
each other and the rest
of the body. “Whole
body” animal studies
help to identify drugs
that can change these
interactions in the context
of a living organism and
thus prevent, reduce, or
eliminate the cancer.
combining Taxus with alcohol.
But it was hard to purify enough
of the compound from the bark to
determine its structure. Stripping
each yew tree produced two kilograms of dried bark, but yielded
just one-half gram of Taxol—and
left the tree dead. This made the
compound much less attractive
as a potential treatment, and by
1967, Taxol had been relegated
to NCI’s back burner. The work
limped slowly along however,
and in 1978 researchers using a
new type of laboratory mouse
model of cancer showed that
Taxol caused regression of mammary tumors.
Before pharmaceutical compa4
nies invest the 10 or more years
it takes to bring a cancer drug
to the market, they like to know
how the drug actually kills cancer cells, i.e. its “mechanism of
action.” No one knew how Taxol
worked until 1979, when research
conducted by Susan Horwitz
showed that it worked in a totally
different manner from any other
known anticancer drug.
The existing drugs either damaged DNA directly, or they
interfered with tubulin, a protein
that is essential for cell division,
or mitosis. Tubulin chains constantly form and un-form (technically stated, they polymerize and
de-polymerize) during mitosis.
Vinca alkaloid drugs prevent
tubulin chain formation, while
Taxol does the opposite, preventing its “un-forming” or disassembly. Both of these interferences
stop cell division and lead to cell
death. (See the sidebar “How
Some Drugs Kill Cancer Cells.”)
It had been years since researchers had discovered a new mechanism in the war on cancer. This
breakthrough generated great
excitement for Taxol, and catapulted it into clinical trials in the
early 1980s for refractory ovarian
cancer, the kind that afflicted Tia
McAlpine.
Overcoming nature’s
scarcity
In a clinical trial, drugs are
judged in part by how many
patients “respond” to it, meaning
whether their tumors shrink by
a significant amount, or at least
stop growing. Participants in the
Taxol trials had a response rate
of 30 percent, an unheard-of rate
How Some Anticancer
Drugs Work
Ideally, anti-cancer drugs should harm only cancer cells and spare normal cells in the
body. Cancer cells differ from normal cells in many ways, but one hallmark is that they
grow and divide rapidly, so many drugs target fast-dividing and fast-growing cells by
disrupting steps in cell division. This disruption damages cells so badly that the cells
“commit suicide”—they initiate a cell death program called apoptosis. Here are
several ways that drugs derived from natural products kill cancer cells.
1) Damage DNA
DNA is usually tightly wound inside the nucleus of our cells, but
it unwinds during cell division. This makes the cell vulnerable to
damage.
• Calicheamicin, a drug isolated from a soil bacterium, binds to
this unwound DNA and cuts apart both strands of the double helix.
2) Interrupt Cell Division (Anti-tubulin)
DNA Duplication
Cell
During cell division (mitosis),
Anti-tubulin-based cancer drugs
Duplicate
disrupt the activity of microtubules
the chromosomes are
Chromosomes
in cell division, causing the cell to die
Nucleus and
duplicated, and a protein
Nuclear membrane
Microtubules
called tubulin pulls a set of
MIT
Prophase:
OSI
Duplicated pairs
S
chromosomes to each end
of chromosomes
condense and the
Metaphase:
membrane
of the cell so that each subsequent nuclear
Tubulin molecules
breaks down
polymerize to form
daughter cell will receive a
microtubules that align
Anaphase:
the chromosomes in
Microtubules
the center of the cell
pull the pairs of
complete set of chromosomes. Tubulin
Telophase:
chromosomes
Chromosomes
apart to opposite
chains continuously assemble and disassemble
decondense and the
poles of the cell
nuclear membrane starts
to reform in preparation
(polymerizes and de-polymerizes) a tubular structure called a
for the division of the cell
microtubule. When drugs prevent this assembly or disassembly, the cell
undergoes apoptosis.
• Vinca alkaloids like vinblastine and vincristine, derived from a periwinkle plant,
cause chaos by binding to tubulin and preventing formation of the microtubule.
• Taxol, derived from the yew tree, does the opposite. It “freezes” the tubulin,
preventing the disassembly of the microtubule.
• Eribulin, a synthetic drug developed from the structure of a marine sponge
compound, appears to prevent both assembly and disassembly.
3) Prevent DNA Repair
DNA damage happens during the normal
course of living, so cells have developed
DNA repair mechanisms to fix the nicks and
mismatches that otherwise accumulate. Some
anti-cancer drugs prevent these DNA repair
mechanisms from functioning properly,
causing cell death.
Some anticancer
drugs prevent the repair
of damage to DNA
Common Types
of DNA Damage
Nucleotide
Mismatch
Nick
DNA Strand
DNA Repair
Enzyme
• Yondelis (trabectedin), a drug
developed from a sea squirt and approved in the USA in 2007, inhibits the
transcription of genes involved in DNA repair. The accumulating DNA damage
stops the cell cycle, activating apoptosis.
• Anthracyclines like doxorubicin, a class of drugs derived from bacteria, inhibit
enzymes called topoisomerase II. These enzymes allow DNA loops to come apart
and reunite in order to express genes or duplicate DNA for cell division. Inhibiting
them prevents the DNA repair required for reuniting the loops.
Breakthroughs in Bioscience
5
for patients with such advanced
tumors who had failed all previous therapies. That result was
promising—too promising. How
could the pharmaceutical industry
possibly produce enough of this
drug to treat thousands of women
with advanced ovarian cancer
without decimating the slowgrowing yew tree population in
the old-growth forests that were
home to the endangered spotted
owl—and an environmental hot
spot? And what if Taxol proved
effective for other cancers too?
That would create even more
unmet demand for the new drug.
Disaster was averted when
researchers developed another,
less environmentally destructive
way to harvest a closely related
compound (10-deacetylbacctin III) from the needles of the
English yew, Taxus baccata.
They chemically modified the
Taxol-like compound to generate the chemical structure of
Taxol. The needles were renewable since the tree could grow
more of them, and clipping them
did not kill the tree. Thanks to
that advance, further clinical trials proceeded, and in 1994 the
FDA approved the semi-synthetic
version, named Paxlitaxel, for
refractory ovarian cancer, and
then a related drug, Taxotere
(docetaxel). Researchers continue
to fine-tune and expand the uses
of these drugs, such as for metastatic breast cancer, AIDS-related
Kaposi’s sarcoma, and some lung
and head-and-neck cancers. Most
recently in June 2010, a semisynthetic taxane drug, Jevtana
(cabazitaxel), was approved for
treating hormone-refractory prostate cancer. To fully take advan-
tage of the power of Taxol, the
drug is also being tested in a new
experimental approach, discussed
below, to target it more exclusively to cancer cells. Too toxic for therapy
An unconfirmed but enticing
legend holds that Alexander the
Great was fatally poisoned in
323 BC by drinking water from
the River Styx, the mythological
river that divides life and death.
The river is thought to be based
on the Mavroneri River in northern Greece, where nearby soils
have traces of a deadly naturally occurring compound called
calicheamicin. Calicheamicin is
produced by a soil bacterium and
is among the most cytotoxic and
potent natural substances known.
Like many initially promising
compounds, and in keeping with
Greek tragedies, its fabled toxicity has proven to be its pharmaceutical downfall, at least temporarily.
example, causes breaks in both
strands of DNA.
Calicheamicin killed cancer
cells, researchers discovered,
but was up to ten thousand times
more toxic than existing chemotherapy drugs. This was also too
toxic to normal cells, so the compound could not gain approval
for clinical use. But what if there
was a way to strategically harness this potent compound by
targeting it specifically to cancer cells? Efforts to accomplish
this have led to an ingenious
new method for targeting drugs
Antibody-targeted
therapies
Targeted drug delivery of highly
toxic compounds builds upon
another approach researchers
were using to fight cancer: monoclonal antibodies. Antibodies are
molecules made by the immune
system that bind to protein “identification tags” called antigens
that are found on the surface
of cells. (The term monoclonal
Figure 3 — What
should drugs target
in cancer cells?
The ideal anticancer drug would
harm only cancer
cells and spare
normal cells in the
body, causing no
side effects. Some
cancer therapeutics
aim at proteins
unique to certain
cancer cells, or that
are more abundant
in cancer cells than
in normal cells.
Most chemotherapies damage dividing cells, since cancer cells typically
divide more rapidly
than normal cells.
This strategy can
harm healthy dividing cells in the liver,
skin, intestine, but
these cells usually
regenerate. Source:
National Cancer
Institute.
Calicheamicin research began
in the 1980s when a scientist collected a soil sample while vacationing in Texas, and his lab later
isolated the compound from the
Micromonospora echinospora
bacterium in the sample. This
compound and another, esperamicin, were the first members in a
class of chemotherapeutics called
enediynes to be fully identified.
These compounds damage the
DNA of a cell’s chromosomes
so badly that the cell is unable
to repair it. This causes the cell
to “commit suicide” by activating a program called apoptosis.
Different agents damage DNA in
different ways; calicheamicin, for
Breakthroughs in Bioscience
and may ultimately revive the
promise of many anticancer compounds deemed too toxic.
6
➊Antibody-Drug Conjugate (ADC)
Antibody
Specific for a tumor-associated
antigen that has restricted
expression on normal cells
Linker
Attaches drug
molecule to the
antibody
Cytotoxic Agent
Designed to kill target
cells when internalized
and released
Antigen
Binding Site
Antigen
Substance recognized
by the antibody
➋ ADC binds to receptor
complex
➌ isADC-receptor
internalized
Nucleus
➍ Cytotoxic agent
is released
Apoptosis
➎ (cell
death)
figure 4 — how antibody-drug conjugates work
Antibody-drug conjugates (ADC) combine a drug with an antibody. Antibodies are
shaped like a Y, with arms that lock onto matching shapes, or antigens, on cells in
a lock and key fashion. Researchers choose an antibody that targets an antigen on
specific cancer cells. They attach linkers to the Y’s stem that hold tightly to a drug
molecule. When the ADC locks on the cancer cell, the cell absorbs it. The linkers are
designed to dissolve or be cut apart inside the cell, which releases the drug molecules.
Once released from the linker, the drug becomes active inside the cancer cell. Adapted
from seattle Genetics by Corporate press.
means these antibodies are all
produced by the same cloned
cells, so they are identical.)
Cancer cells have unique antigens that distinguish them from
healthy cells. Thus antibodies
that bind to the cancer antigens
allow for the targeting of cancer
cells rather than normal cells.
Among the most widely used
antibody therapies are Rituxan
(for treatment of non-Hodgkin’s
Breakthroughs in Bioscience
lymphoma), Erubitux (for
colorectal cancer), and Herceptin
(for metastatic breast cancer).
These antibody therapies cause
the immune system to attack
cancer cells by triggering an
immune response. Even though
they have the advantage of specificity, monoclonal antibodies are
only effective in treating a few
cancers. Cytotoxic compounds,
on the other hand, have the
7
advantage of being much more
potent, but they are not specific
and decimate healthy cells, often
damaging the liver, kidney, and
bone marrow. So the idea of targeted drug delivery was to combine the specificity of antibodies with the cancer cell-killing
power of compounds that are too
toxic for patients when administered without targeting. These
cancer-seeking missiles are called
antibody-drug conjugates (ADC),
and they essentially shepherd
inactive forms of highly potent
drugs into the unsuspecting cancer cell. Exposure to the internal
environment of the cell then triggers the conversion of the drug to
its active form.
The first attempts at employing
ADCs used clinically approved
drugs derived from natural products, such as vinca alkaloids and
doxorubicin, a compound that
Italian researchers searching
for anticancer molecules in the
1950’s isolated from soil bacterium near a 13th century castle
on the Adriatic Sea. Doxorubicin
is the basis for drugs used in
combination to treat a number
of cancers. But results of these
ADCs were marginal because
the drugs were themselves not
very potent. Then researchers
proposed using the more potent
but unapproved compound, calicheamicin. The calicheamicinbased ADC, called Mylotarg, was
targeted to the aberrant cells in
acute myeloid leukemia (AML)
and was approved for patients
with advanced AML in 2000.
Ten years later, however, the
drug was pulled off the market because of concerns about
Table 1: Antibody-Drug Conjugates Under Development
Name of Conjugate
Antibody Target
Drug Compound
Natural Source
Mechanism of Action
Cancers Being Tested
Inotuzumab
ozogamicin
CD22 (immune cell
regulator)
Calcheamicin
(ozogamicin)
Bacterium,
Micromonospora
echinospora
Breaks DNA
Acute lymphocytic
leukemia
Trastuzumab-mertansine
(Herceptin-DM1)
HER2 receptor
Maytansine
derivative
Plant in the staff
vine family,
Celastraceae.
Inhibits tubulin
assembly during cell
division
Breast cancer
safety and insufficient efficacy
in patients with advanced AML.
Despite the cleverness of the
ADC approach, the actual execution is not a trivial task. The
antibody-drug linkage has to be
stable within the bloodstream so
as not to release the cytotoxic
compound prematurely and offtarget. Further, once inside the
cancer cell, the drug must be
resistant to being pumped out, a
trick often used by drug-resistant
forms of cancer. Since the development of Mylotarg, researchers
have made important advances in
the design of ADCs. Mylotarg’s
example showed that this new
approach for targeted drug delivery could work. In 2011, the
FDA approved another monoclonal antibody linked to auristatin,
a drug derived from dolstatin 10,
a marine natural product. This
conjugate, named Adcetris (brentuximab vedotin), is approved for
treating two types of lymphoma
and is in clinical trials for other
lymphatic cancers. Many other
ADCs are now in development
(see Table 1), and scientists
hope that the ability to tame very
potent cytotoxic compounds may
rescue discarded drug candidates
that failed because they were
too toxic when delivered the old
fashioned way.
Breakthroughs in Bioscience
Figure 5 — Plaque for Rapamycin on Easter Island
Studying rapamycin, a natural product isolated in 1965 from soil bacterium on Easter
Island, led researchers to entirely new strategies for cancer therapies that target
changes in cancer cell metabolism. Source: Anypodetos via Wikipedia.
Figure 6 — Marine sponge: natural source for Eribulin. The marine sponge,
Halichondria okadai, is the source for the compound that was developed as the cancer drug Eribulin. This drug interferes with the tubulin molecule during cell division.
Eribulin is now made synthetically and was approved in November 2010 to treat
metastatic breast cancer. Image courtesy of Dennis Sabo. Image courtesy of Richard
Seaman.
8
Rapamycin: it’s
complicated
Targeted Therapies
Cancer is not one disease, but many. This is not only because cancers in different organs—
lungs, breast, brain, liver, blood, etc—behave differently. Even cancers in the same organ
are driven by different genes and have different responses to the same drug. Mutations
in many genes involved in growth signaling pathways can cause cancer. These cancerpromoting, or oncogenic, mutations provide an opportunity for therapeutic intervention
because they distinguish the cancer cell from the normal cell. Targeting a specific mutation
causes fewer side effects than disrupting cell division in general, as most chemotherapies
do, which also harms normal fast-growing tissue like skin and the lining of the stomach and
intestines. This alternate approach to anti-cancer drugs is called targeted therapy.
The first targeted therapy, from 1998, was Herceptin (trastuzumab), an antibody treatment
for metastatic breast cancer patients whose tumors have an excess of a protein called HER2.
This protein is a receptor for growth signals, and its amplification makes the cancer grow
more aggressively. Herceptin is shaped to lock on to the receptor, blocking it to inhibit the
growth signal. Gleevec (imatinib), approved in 2001 for chronic myelogenous leukemia
(CML), was the first to target tyrosine kinases, which are proteins that activate pathways
that relay growth signals. Gleevec inhibits a tyrosine kinase called bcr-abl. Other tyrosine
kinases are involved in other cancer subtypes, and the roster of targeted therapies keeps
growing. Often only a small subset of patients with, say, lung cancer, have tumors with the
targeted mutation. If they do, drug targeting can work rapidly to shrink or even completely
destroy tumors. If they do not, the drugs are ineffective. Unfortunately, cancers easily
“escape” targeted therapies by using alternate growth pathways, causing drug resistance. So
researchers are combining several targeted therapies to prevent or delay resistance.
Genetic variations do more than subdivide cancers within one organ. They sometimes
unite tumors in different organs. For example, HER2 amplification can occur in the lung,
esophagus, salivary glands and ovaries as well as the breast. So Herceptin is being explored
for those cancers too. Gleevec, by happenstance, targets a mutation in the c-kit protein
involved in about 10 percent of gastrointestinal stromal tumors (GIST), so it is approved for
this cancer as well as CML. Because of the significance of specific mutations to therapy,
physicians may “genotype” or genetically test a patient’s tumor to learn if a targeted
therapy matches it—the essence of personalized cancer therapy.
Interestingly, targeted therapies are small molecules that mimic natural molecules used
in the cell. Gleevec, for example, mimics ATP, the cell’s energy carrier. So while these
targeted therapies are not derived from trees, sponges or bacteria, they are inspired by
nature’s prodigious designs.
An Antibody Called Herceptin
Breast cancer
patient
Growth
factor
Herceptin
blocks receptor
Growth
slows
Breakthroughs in Bioscience
9
The natural products developed into anticancer therapies
discussed so far work mainly by
killing dividing cells. But other
natural products with anticancer properties target different
cellular processes. One of the
most complex examples of this
came to light from studying a
compound called rapamycin. In
1965, researchers were looking
for antibiotics in soil bacteria on
the island of Rapa Nui (Easter
Island) when they isolated this
compound, which they named
rapamycin after the island. At
first, rapamycin was investigated
as an antifungal medication, but
was later approved as an immunosuppressant to prevent the
rejection of transplanted organs.
It also inhibits cell proliferation, and so it was developed as
a cancer drug, Temsirolimus.
Currently six approved drugs
and three candidate drugs are
derived from rapamycin, one of
which is being investigated as a
potential treatment in autism and
Alzheimer’s disease, as well as
for HIV infections.
What could account for such
diverse effects from one compound? The answer lies in the
importance of rapamycin’s target in the cell, which researchers named mammalian Target
of Rapamycin, or mTOR. The
mTOR pathway is involved in
many fundamental biological
processes. Among other things,
it is a master regulator of cellular
metabolism and coordinates cell
growth and proliferation with
the availability of nutrients and
oxygen. In the past decades,
researchers have come to appreciate that metabolism in cancer
cells differs from that of normal
cells. Cancer cells consume
much more glucose, and they
metabolize it using a different
process that produces more of the
proteins, lipids, and other “building blocks” required to support
rapidly growing and dividing
cells. Many researchers think that
shutting off this super-charged
metabolism could provide an
entirely new approach to anticancer therapy. Rapamycin inhibits
mTOR, which suppresses some
aspects of cancer metabolism and
is effective against several cancers. Researchers are also developing drugs to target other points
in the metabolic pathways of cancer cells. This research on cancer
metabolism runs parallel to other
work attacking nodes in specific
cancers’ growth pathways, as discussed in the sidebar “Targeted
Therapies.”
Into the deep
If finding natural compounds
growing on land is hard, imagine
searching for them in deep, dark,
shark-infested ocean waters.
There is little folklore about
medicines from the sea, probably because exploration was
confined to where humans could
swim or fish. But in the past 50
years, submersibles have opened
up these previously inaccessible
environments, and new molecular
technologies are revealing the
secrets in the organisms found
there.
In the mid-1980s, the NCI
began funding research and
Breakthroughs in Bioscience
large-scale collection projects
to systematically explore the
potential of drugs from the sea. It
seemed a promising place to look
for new anticancer compounds,
since organisms that have adapted to odd ecosystems, like highpressure zones and sulfurous
deep sea vents, have evolved
novel proteins, with unusual biological activity, to survive. And
because sessile marine creatures
like sea sponges encounter so
many different types of predators,
they have concocted ingenious
toxins and other defensive—or
offensive—compounds to protect
themselves.
The first new chemotherapeutic produced directly from the
sea came from the tunicate (sea
squirt) Ecteinascidia turbinate.
That drug, Yondelis (trabectedin), inhibits the genes involved
in repairing damaged DNA.
Without this DNA repair process,
the damage accumulates, and
that triggers the cell death program, apoptosis. Yondelis was
approved in the United Kingdom
and Europe in 2007 for the treatment of sarcoma and is in clinical trials in the United States for
breast and prostate cancers and
pediatric sarcomas as well.
Eribulin, the second approved
chemotherapeutic from the sea,
involved a multidisciplinary,
multinational drug development
effort and technological tour
de force requiring aquaculture,
and an interplay of academic,
industrial, and government labs
on three continents. This effort
began in 1986 when Japanese
researchers isolated a compound called halichondrin from
a sponge (Halichondria okadai)
living off the coast of Japan.
Like Taxol, halichondrin interferes with tubulin, the protein
strands that pull the chromosomes around during mitosis
or cell division, but in a unique
Table 2: Drugs under Development from the Sea
Drug
Natural Source
Mechanism of Action
Cancers Being Tested
Bryostatin 1
Marine moss creature,
Bugula neritina
Modulates protein
kinase C
Various cancers
Aplidin
Mediterranean tunicate,
Aplidium albicans
Inhibits protein synthesis
and VEGFR1
Multiple myeloma
Irvalec
Hawaiian marine mollusk Elysian rufescens
Damages plasma membranes
Various cancers
Zalypsis
Synthetic related
to Jorumycin and
Renieramycins, from
mollusks and sponges
Causes DNA doublestrand breaks and other
mechanisms
Multiple myeloma
PM-060184
Synthetic modification
of a marine-derived
compound similar to
Zalypsis
Causes DNA doublestrand breaks
Solid tumors
Marizomib
Marine bacterium,
Salinospora tropica
As a proteasome inhibitor, prevents breakdown
of proteins
Multiple myeloma, lymphomas, leukemias, and
solid tumors
Plinabulin
Halimide isolated from
a marine Aspergillus
fungus
Disrupts established
tumor vasculature
Non-small cell lung
cancer
10
way. It binds to the microtubules
formed by tubulin at different
sites than other drugs, and prevents the strands from growing or
decreasing in size.
Because the marine sponge
that produces the compound
is rare and cannot be cultured
or grown in a lab, researchers
looked for similar compounds
in related species, as had been
done to overcome a similar problem with Taxol. They found the
halichondrin-like compounds in
a sponge growing off the coast of
New Zealand that they were able
to “farm” at shallow depths, the
first time this had been achieved.
However, the compound was
simply too huge–more than twice
the size of a typical drug molecule.
This unwieldy compound also
proved to be incredibly complex,
with a unique chemical structure.
Starting in 1987, Yoshito Kishi,
a chemist at Harvard University,
undertook the challenge of synthesizing halichondrin and eventually identified the biologically
active part. He worked with a
Japanese pharmaceutical company to synthesize this component,
which they called Eribulin. The
NCI entered Eribulin into clinical trials in 2002, and the FDA
approved it for metastatic breast
cancer in patients who were unresponsive to other therapies in
November 2010. The drug is now
being tested in other cancers as
well.
A third, entirely different type
of marine compound, bryostatin
1, was discovered in the late
1960s when G. Robert Pettit of
Arizona State University, workBreakthroughs in Bioscience
ing with the NCI early collection
programs, extracted it from a
reddish-purple moss-like marine
creature, Bugula neritina, in the
phylum Bryozoa. Bryostatin
1 modulates protein kinase C,
which is involved in many cellular functions. The compound
appears to work synergistically
with other cancer drugs but is
less effective as a stand-alone
therapy. It is being tested in
combination with other cytotoxic
drugs in a variety of cancers.
Interestingly, it also appears to
enhance memory and is being
explored as a treatment for
Alzheimer’s disease.
A variety of drug candidates,
coming either directly from
marine sources or modified
marine-sourced chemical structures, are in the clinical development pipeline as antitumor
agents. (See Table 2.) Still, of
the 25,000 marine-sourced compounds that researchers have
described to date, only around
20–a mere 0.1%–have reached
clinical trials for human diseases,
with seven approved by the FDA
or its international equivalents.
And so, we have only just begun
the search for medicinal compounds in the sea!
Nature’s designs: tried
and still true
To be sure, the development
of anticancer drugs from natural
products is a long and arduous
journey of discovery, testing, and
development. In the late 1980s,
many researchers hoped that
screening small synthetic molecules for anticancer properties
could bring more new drugs to
11
Metabolites
in Our
Future
In the future, we might be able to bypass
delicate or difficult-to-acquire plants
and animals altogether when developing
drugs from natural products. It now
appears that many natural compounds
with medicinal properties are actually
made by microbes living on the plant
or animal, possibly even in the case
of Taxol and Eribulin. The larger
organism may merely be the host to
the organism, a bacteria or fungi, for
example, making the active compound.
The microorganisms living on plants
and animals may produce poisonous
compounds that prevent their hosts from
being eaten by insects or bears, sharks,
or turtles.
Such compounds produced to help
an organism defend itself are called
“secondary metabolites.” (Primary
metabolites are those compounds
required to actually survive, such as
to digest food or take in oxygen.)
Secondary metabolites may be
activated as a “last resort” defense and
are normally silent in the laboratory.
The implication of these secondary
metabolites for drug development is
huge. If researchers could learn to
activate these silent, last-resort genes in
the laboratory, they could generate new
products to investigate for new anticancer properties – and perhaps create
inexpensive shortcuts to procuring these
valuable compounds for patients.
the market more quickly. But that
approach was not very effective.
Many of these small molecules
failed in pre-clinical trials, while
natural products and their derivatives are still inspiring new anticancer drugs. In 2007, for example, the FDA approved the first
of a new class of anticancer drugs
called epothilones, isolated from
a gliding bacterium (Sorangium
cellulosum). One drug, Ixempra
ways with the cellular processes
involved in health and disease.
And so, 20 years after moving
away from the search for natural product-based drugs, many
researchers have a renewed interest in exploring natural products,
as well as complex molecules
that have structural similarities to
them.
(ixabepilone), is being used to
treat breast cancer that does
not respond to other therapies
and works similarly to Taxol in
“freezing” tubulin to prevent cell
division. More recently five antitumor drugs approved in 2010
stemmed from natural product
research. (See Table 3.)
As difficult as natural products
may be to develop as drugs, they
frequently have advantages over
simpler small molecules. Their
biologically active parts are
complex structures that interact
in more biologically relevant
Anticancer drugs based on natural products have carried much
of the load during the modern
war on cancer, and they have
made a huge difference for millions of cancer patients. But the
Table 3: Recently Approved Anticancer Drugs from Natural Compounds
Year
Drug
Natural Source
Cancer Treated
2010
Eribulin (halichondrin)
Halichondria okadai
(marine sponge)
Metastatic breast cancer
2010
Istodax (romidepsin)
Chromobacterium violaceum (soil bacterium)
Cutaneous T-cell lymphoma
2010
Javlor (vinflunine)
Vinca (periwinkle)
Cancer of urothelial tract
2010
Jevtana (cabazitaxel)
Yew tree
Prostate cancer
2010
Mepact (mifamurtide)
Modified peptide from the
cell wall of a bacterium
Osteosarcoma
2011
Adcetris (brentuximab
vedotin)
Antibody-drug conjugate
with auristatin, derivative
of dolstatin 10, from a
shell-less sea mollusk
Hodgkin’s lymphoma and
anaplastic large cell lymphoma
2012
Kyprolis (carfilzomib)
Modification of a bacterial
proteasome inhibitor
Multiple myeloma
Breakthroughs in Bioscience
12
legions of cancer patients who
still have no effective therapy
mean that victory against cancer
is still far off, and natural compounds are likely to continue to
play important roles in the ongoing battles. With new approaches
to identifying anticancer compounds and new technologies
for investigating the interaction
of drug molecules with cancer
cells, we can hopefully bring new
drugs to the medicine cabinets of
patients in need.
Additional suggested reading:
Cragg, Gordon M., David G. I. Kingston, and David J. Newman+. (Eds) Anticancer Agents
from Natural Products, 2nd Edition, CRC Press, 2012.
Goodman, Jordan, and Vivien Walsh. The Story of Taxol: Nature and Politics in the Pursuit of
an Anti-Cancer Drug. Cambridge University Press, 2006.
Iyer, U, and Vivek J. Kadambi. “Antibody Drug Conjugates - Trojan Horses in the War on
Cancer,” Journal of Pharmacological and Toxicological Methods 64, no. 3 (December 2011):
207–212.
Kroll, David. “Drugs from the Crucible of Nature,” Scientific American Blog Network,
August 2, 2011.
McGrogan, Barbara T., Breege Gilmartin, Desmond N. Carney, and Amanda McCann.
“Taxanes, Microtubules and Chemoresistant Breast Cancer.” Biochimica Et Biophysica Acta
(BBA) - Reviews on Cancer 1785, no. 2 (April 2008): 96–132.
Newman, David J., and Gordon M. Cragg. “Natural Products as Sources of New Drugs over
the 30 Years from 1981 to 2010.” Journal of Natural Products 75, no. 3 (March 23, 2012):
311–335.
The Breakthroughs in Bioscience
Swinney, David C., and Jason Anthony. “How Were New Medicines Discovered?” Nature
Reviews Drug Discovery 10, no. 7 (June 24, 2011): 507–519.
series is a collection of illustrat-
Biographies:
ed articles that explain recent
developments in basic biomedical research and how they are
important to society. Electronic
versions of the articles are available in html and pdf format at
the Breakthroughs in Bioscience
website at: www.faseb.org
Cathryn M. Delude, of Andover, Massachusetts, writes about science and medicine
for magazines and newspapers. She has written for FASEB in the past, and her articles have
appeared in Nature Outlook, AACR’s Cancer Discovery, Los Angeles Times, Boston Globe,
New York Times, Scientific American, The Scientist, Proto: Dispatches from the Frontiers
of Medicine, and other publications on topics including neuroscience, cancer, molecular
biology, microbiology, infectious diseases, water, energy, and civil and environmental
engineering. She has additionally written for the Howard Hughes Medical Institute, Harvard
Health Publications, Harvard School of Public Health, Massachusetts General Hospital,
Massachusetts Institute of Technology, Dana Farber Cancer Center, Stowers Institute for
Medical Research, and the National Institutes of Health - Office of Science Education.
John A. Beutler, PhD, is a natural products chemist with broad interests in cancer
biology and drug screening and development. He works in the Molecular Targets Laboratory
of the National Cancer Institute Center for Cancer Research in Frederick, MD, and is
currently pursuing the development of natural product drug candidates for brain and kidney
cancer. He has published over 100 scientific papers, is Co-editor of the Review of Natural
Products, and was President of the American Society of Pharmacognosy in 2010-11. His
undergraduate degree was awarded by Vassar College, and his MS and PhD degrees were
awarded by the Philadelphia College of Pharmacy & Science. Dr. Beutler went on to
complete his postdoctoral training at Northeastern University and the University of Texas
Medical School.
Breakthroughs in Bioscience
13
Published
2013
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