Scientists Protect Against
Internal Terrorists
March, 2004 La Jolla Light
By Jim Kelly
Rising like
promises from the valley edge of
the Torrey Pines plateau are two
buildings, one black and one white.
Inside these buildings, brain
trusts of scientists are engaged in
a war on terrorism.
The terrorists
come in many forms but they all
have one name, cancer.
This war
is being waged by scientists from
the Sidney Kimmel Cancer Center (SKCC).
Affiliated with
Sharp HealthCare, the Sidney Kimmel
Cancer Center has accomplished so many breakthroughs
in medical science in its 13 years
of existence, seven for-profit
corporations have been spun off to
bring their discoveries to the
suffering public.
Avoiding
harming normal tissue
The commanding
general in this conflict is Albert
Deisseroth, M.D., Ph.D., president
and CEO of SKCC. "Most cancer
treatments in the past were based
on therapy that was destructive,"
Deisseroth said in a recent
interview with The Light.
"Cut it out,
burn it with radiation or
administer intravenous or oral
toxins that would, not only kill
the cancer cells but would also
damage normal tissue."
What SKCC is
trying to do is to distinguish what
is different about cancer tissue.
"Knowing how it is different is
very important if you are thinking
of targeting it with therapy.
"If
we can identify the signature of
cancer cells we can target it with
a guidance system that avoids
normal tissue," Deisseroth said.
Deisseroth and
his team of scientists are
concentrating on four areas of
research, vascular targeting
(cutting off the blood supply of a
tumor), cancer cell biology,
genomics (studying the genetic
material of an organism) and
immunotherapeutic targeting.
According to Per
Borgstrom, Ph.D., a researcher in
vascular targeting working in the
institute’s black building, the
potential treatment being developed
would be helpful with cancers when
they metastasize (form secondary
tumors and spread throughout the
body).
"Through genetic
identification we can find blood
vessels feeding very small tumors," Borgstrom said. "Then we can target
these blood vessels and kill them."
Another area of
targeting, proteomics, is being
done by Dr. Jan Schnitzer,
scientific director of SKCC. With
his boyish appeal and a easy good
nature, Schnitzer looks like he
could be playing in an
over-the-line tournament.
But what
Schnitzer is doing is not a game.
Using techniques newly developed in
his lab at SKCC to map the proteins
at the surface of blood vessels in
tumors, he is able to discover new
targets that facilitate rapid
delivery of drugs directly to
tumors which can vastly decrease
the dosage needed in therapy.
"In traditional
chemotherapy, small toxic molecules
go into the circulation system and,
because they are small, they are
able to get access throughout the
body. That leads to well-known and
unwanted toxicity.
Through its effect
on highly proliferating cells,
chemotherapy has the desired
greater toxic effect on tumor cells
but unfortunately at the price of
some normal cells, like in the skin
and gut, that also divide rapidly.
This creates a
small therapeutic window of
toxicity that is pretty crude and
rude to the patient."
Cancer's Holy
Grail
From these
obvious therapeutic shortcomings, a
new idea developed that envisioned
direct targeting of toxic agents to
the tumor cells to create better
therapies beyond typical
chemotherapeutic agents. This
"magic bullet" concept has long
been a Holy Grail in medicine's
crusade against cancer for almost a
century.
With the advent
of new biotechnology in the 1970s
to make antibodies (large proteins
normally made by the body to attack
infective agents), a means to
target tumor cells specifically
became possible.
But as is
usually the case in the scientific
discovery process, the huge wave of
initial enthusiasm became tempered
over the next two decades by
unforeseen realities and barriers
to success.
Antibodies when
injected into the blood have a hard
time getting inside the tumors.
Until recently it was also thought
that because all cancer cells even
within a single tumor are not
alike, no one treatment was
believed possible.
Work in Dr.
Schnitzer’s lab may revive the
magic bullet strategy but in a new
direction not originally imagined.
Like any normal organ of the body,
tumors require blood vessels for
their growth.
Blood vessels
are lined with endothelial cells
that form a barrier prevented drugs
such as antibodies to reach the
intended target for destruction,
namely the cancer cell inside the
tumor.
For
over a decade, Schnitzer has been
working on ways not only to target
and destroy the blood vessels of
tumors but perhaps more importantly
also to delivery drugs to cancer
cells that lie on the other side of
the endothelial cell barrier.
Because these
tumors are so hard to get to, past
antibody-toxins and even
chemotherapies have less than one
percent effectiveness.
In other
words, more than 99 percent of the
toxin does not enter into the tumor
but rather circulates throughout
the rest of the body to cause the
patient to suffer greatly.
But
instead of targeting the tumor cell
surface as envisaged for the
original "magic bullet", Schnitzer's lab has been working on
targeting the surface of the
endothelial cells.
"We're talking
about changing the bull’s eye,"
Schnitzer said. By doing this, his
researchers have been able to
develop antibodies specifically
coded to reach certain endothelial
cells increasing the amount of
toxin reaching the cancer cell by
more than 100-fold.
His lab has
discovered a new pathway mediated
by special endothelial vesicles
called caveolae (means "little
caves") to get antibodies through
the blood vessel wall to reach the
insides of the tumors.
According to Schnitzer, "Tissue penetration
across the endothelial barrier is
critical for drug delivery and more
effective anti-cancer treatments."
Designer
drugs
It appears to be
possible that a "designer drug" can
be developed to work on most types
of solid tumors. In addition to
this procedure's accuracy in
targeting tumors, it is
fast-acting. Within 60 seconds of
introducing the drug the targeted
area is being reached. The
efficiency and speed of "changing
the bull’s eye" keeps the rest of
the body from being adversely
affected by toxins.
This
break-through in cancer research
adheres to one of Deisseroth's main
principles of destroying the cancer
without harming the patient.
Because of Schnitzer's work, a much
smaller dose of toxic agent can be
administered and previous drugs,
discarded because they were
considered too deadly at the high
doses required, can be
re-introduced into future treatment
programs.
Next door, in
the white building, Deisseroth’s
lab has come up with equally
impressive results. In a report
released this week in the
prestigious "Proceedings of the
National Academy of Sciences," SKCC
announced a new virus-based vaccine
for cancer.
"The vaccine is
based on the principal that a virus
is one of the best ways to activate
the cells of the immune response
against cancer cells," explained
Deisseroth.
By using a
safely-modified cold virus
developed by the Deisseroth lab at
SKCC called an adenovirus, the
team, consisting of Lixin Zhang,
Yucheng Tang, Hakan Akbulut, Daniel
Zelterman, Phyllis-Jean Linton and
Albert B. Deisseroth, has found
they can direct the attention of
the immune defense system against a
marker.
This marker is
present at high levels on cancers
of the breast, ovary, lung, colon
and prostate.
The immune system
normally ignores cancer cells
because they have the same surface
properties as normal cells and immunotherapists have long been
challenged to find a way to alert
the body to the presence of these
dangerous growths.
However, after
two injections of the adenovirus
Deisseroth’s lab has created, the
sentinel cells of the immune
response, the dendritic cells, are
alerted so they can recruit the "effector"
cells of the immune system to
attack and kill the cancer cells.
This adenovirus,
referred to as a "vector," has been
effective in activating resistance
to the growth of cancer cells
lasting up to a year.
Although it was
created as a prophylactic against
cancer, the vaccine has been
injected into test animals with an
established growth of cancer cells
and their tumors have been
suppressed.
It has also been
possible to transfer the resistance
to these cancer cells by injecting
spleen cells from one test animal
to another.
In addition to
making available a vaccine for
protection against cancer, the
vector might also be of value in
the treatment of cancers that recur
after surgery and are unresponsive
to standard treatments of
chemotherapy and hormonal therapy.
Happy
scientists
The curious
thing about SKCC is not its level
of success against cancer, but its
ability to attract so many
world-class scientists. Jay
Jeffcoat, senior vice president for
community, public and governmental
relations said it was more than the
La Jolla weather.
"The center
provides a place where scientists
are free to pursue pure research,"
he explained. "They also can
experience an immediate application
of their work."
To underline his
belief, Jeffcoat pointed out a
recent finding by one of the
center’s scientists, Michael
McClelland. McClelland’s team
unraveled the genetic code of a
virulent Salmonella that causes
food poisoning.
His research is,
hopefully, the first step in
developing a vaccine effective
enough to help doctors eradicate
Salmonella infection worldwide.
"Because of the
center’s and Dr. Deisseroth’s
attitudes toward pure research, the
work to unravel this code was not
just permitted, it was encouraged,
even though it was outside the
strict definition of cancer
research." Jeffcoat said.
Deisseroth
echoed Jeffcoat's feelings about
SKCC. "All scientists want to feel
their lives have been valuable to
other people," he said.
"Researchers who come here can see
a transition from discovery of
knowledge into treatment and
therapy."
The future for
SKCC seems as bright as its past.
Through a generous grant from
Sidney Kimmel, two parcels of land
above the existing buildings have
been purchased and new research
facilities are in the planning
stages.
But SKCC still
needs the financial assistance of
the worldwide community it serves
in order to expand. According to
Deisseroth, cancer is the leading
consumer of the healthcare dollar
and the scientists at SKCC have a
moral obligation to fight it.
In
the 2002 Annual Report for SKCC he
wrote, "If we work together, the
result will be the most precious
gift of all—the gift of life."
For more information, go to
Sidney Kimmel Cancer Center.
