"New Drugs New Hope" Boston Globe - Part 2
Here is part two of five, of tremendous research from the Boston Globe:
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CANCER: TURNING THE CORNER New drugs, new hope
By Richard Saltus, Globe Staff, 08/03/98
Second of five parts
HOUSTON - INSIDE JIM Hassmann's bones, out-of-control white blood cells had
taken over. Dividing unchecked, they were squeezing out the marrow that
produces life-sustaining red blood cells.
Conventional drugs failed to slow his rampaging chronic lymphocytic
leukemia, or CLL. ''The hematologist said there was nothing else to help
me, that I was at end-stage,'' recalls Hassmann, 54, who was breathless,
tired, and sick. ''And I was making end-stage plans.''
As a last resort, the Houston man was referred earlier this year to the
vast M.D. Anderson Cancer Center here, where besides standard treatment,
patients can volunteer for a wide range of experimental therapies, from
cancer vaccines to gene therapy.
The first two drugs he tried failed. But in April, Hassmann was switched to
a drug called Campath-1H, made by a Cambridge, Mass., biotech company,
LeukoSite. The drug worked like a ''smart bomb'' to knock out the cancer
cells while sparing the marrow that makes new normal white cells. And
unlike most standard chemotherapies, it didn't cause dangerous, toxic side
''I was feeling better within a week,'' says Hassmann, astonished and
grateful after a course of 12 weekly treatments. ''I came there with no
hope. Now this could be good for many years.''
How long Hassman's new lease on life will continue is unknown. Like dozens
of other novel anticancer agents that have prompted a surge of optimism in
the field, Campath-1H is still in early testing.
What is clear, however, is that in 1998, there is marked optimism about
this new generation of ''targeted'' therapies aimed at controlling cancer
with vastly more precise and less toxic drugs than those now available.
''We've pushed [conventional] chemotherapy about as far as it can go,''
says Dr. John Mendelsohn, a molecular biologist and president of M.D.
Anderson. ''It's possible we'll be able to discover new chemotherapy
agents, but we think the targeting of oncogenes or tumor suppressor genes''
that malfunction in cancer cells ''is another major attack we can make'' on
The cancer center, one of the nation's two largest (the other is Memorial
Sloan-Kettering in New York), houses 800 faculty scientists and treats
65,000 patients a year. There are 494 clinical trials in progress here,
including a broad sampling of the novel cancer therapies that have moved
into the spotlight in the last year.
Patients come to Houston from all over, many of them staying in high-rise
hotels that loom over the enormous Texas Medical Center in which M.D.
Anderson is located. In various clinics, they sit waiting for treatments,
undergoing infusions of drugs through intravenous lines, or nervously
anticipating lab results.
Some, like Hassmann, are receiving drugs based on monoclonal antibodies -
engineered proteins that recognize and latch onto specific cancer cells.
Other drugs are designed to block cancerous growth signals from reaching
the receivers on the surface of cells or inside them - like filling a
keyhole with gum so the key won't fit, as one researcher put it.
Others have volunteered for tests of angiogenesis inhibitors. These drugs
disrupt the network of tiny blood vessels a tumor needs to grow, thus
halting or shrinking the tumor. In early human testing these inhibitors
have produced mixed results, but the most powerful ones are not yet ready
for patient trials.
Still other patients, including some with lung, head, and neck cancers, are
undergoing gene therapy. Dr. Jack Roth, chairman of thoracic surgery at
M.D. Anderson, is leading trials in which a gene that is often defective in
cancer cells, called P53, is being ferried into tumor cells by means of a
virus, in hopes of halting malignant growth.
It is P53's job to detect cells with damaged DNA, and either keep them from
dividing until they are repaired, or nudge them along a path to programmed
self-destruction before they can do harm. Mutant P53 genes, by contrast,
allow damaged cells to keep on reproducing, which can lead to cancer as the
cells accumulate genetic damage.
''If you restore P53 function'' with gene therapy, ''it could trigger this
cell death'' and turn off cancerous growth, Roth says. The therapy appears
safe and has shown some activity against tumors in early tests, he adds.
Strategy takes aim at broken cells
Another strategy aims not to repair cells with broken P53s, but to wipe
them out. A bioengineered virus called ONYX-015 specifically attacks and
kills cells with mutant P53 genes. Scientists reported this spring that in
combination with two standard chemotherapy drugs, the virus has shrunk
tumors of the head and neck in 9 out of 10 patients in early trials.
Cancer vaccines - the name for a strategy of revving up the immune system
to attack cancer cells - are also being tested here and at a number of
academic centers and biotech companies. Efforts to harness the immune
system to fight cancer has had a long history and few real triumphs, but
scientists now know more about how the complex immune defenses work and are
more optimistic that selective and powerful vaccines can be made.
One vaccine that mobilizes the immune system against deadly melanoma is
heading toward possible approval in Europe and Canada by the end of the
year and perhaps next year in the United States. Called Melacine, it has
been tested in patients with advanced melanoma who have dismal prognoses.
It has proven to be as effective in extending survival by a few months as
is the standard four-drug chemotherapy treatment. But Melacine is much less
punishing in its side effects, say officials of RIBI ImmunoChem Research,
Inc., the vaccine's makers.
In contrast to the broadly toxic chemotherapies in use today, the new
agents have been precisely designed to attack, or in some cases, correct,
specific genetic changes that turn normal cells into malignant ones.
''Up to now, we have cured a series of cancers that affect young people,''
says Dr. Donald Coffey, of the Johns Hopkins Cancer Center, referring to
diseases like leukemia and Hodgkin's disease in which the war on cancer has
had its greatest triumphs to date. ''We did this with drugs that blocked
DNA synthesis'' - meaning they killed tumor cells, but often hammered
normal cells as well, causing terrible side effects.
But now, scientists are developing drugs aimed at blocking the effects of
mutant, cancer-causing oncogenes, restoring broken tumor-suppressor genes,
and overcoming malfunctioning DNA-repair genes. They hope these therapies
will bring outlaw cancer cells back into good behavior or prod irrevocably
damaged cells into apoptosis, or cell suicide.
If conventional chemo is like bombing an entire city to kill off a
guerrilla force, the newer drugs aim to pick off the enemy and spare the
''I've never seen so many ways to attack cancer,'' says Coffey. Indeed, a
survey this year by an industry group showed that of 350 biotech drugs
under development, 151 - more than one-third - target cancer. There were 30
for melanoma alone, 20 for colo-rectal cancer, and 13 each for prostate and
And, as reports at this spring's meeting of the American Society of
Clinical Oncology reflected, the early tests of many of these agents are
''I've never seen so many positive results in my life,'' says Dr. Dan Von
Hoff, founder of ILEX Pharmaceuticals and an oncologist at the San Antonio
Cancer Institute. ''The biology is beginning to pay off. Now you can sit
down and look a patient in the eye and say there's a good chance of this
doing you good.''
Despite a flurry of media reports this spring proclaiming that a cancer
''cure'' might be at hand, few scientists will touch that word. Sobered by
decades of experience with cancer's Houdini-like ability to escape and
survive, researchers say the new agents may realistically prove more
successful at taming cancer than destroying it.
''We may have cures someday,'' says Samuel Waksal, president of ImClone
Systems Inc. in New York, which is developing targeted cancer therapies,
''but the types of approaches we're developing now may make cancer a
chronic disease. We would like to kill every cancer cell, but we're
recognizing that if you can keep people alive for 30 more years, using
drugs with few side effects - that's pretty dramatic.
''And,'' he adds, ''that's a goal that is achievable in the near term.''
Even in the next two or three years, ''the world [of cancer treatment] is
going to change.''
For ethical reasons, the newest drugs are tried first in patients with
hopelessly advanced cancer. Despite the grim odds, one such drug is already
sparking a glimmer of hope for patients with aggressive, incurable brain
tumors called glioblastomas. The drug, called SU101, blocks an overactive
cell growth-signaling pathway in brain cells and has kept a few patients
alive for one or two years. Under normal circumstances, they would have
died within three months, says Dr. Eric Wong, a neuro-oncologist at
Boston's Beth Israel Deaconess Medical Center, where the drug is about to
Last month, Nelba MacMurdo, 66, of Canton, finished her first seven-week
course of SU101: Her children had read about the experimental drug in a
newsmagazine and sought out Wong. Whether it has affected the brain tumor
whose tentacles couldn't be surgically removed wasn't immediately clear.
But her daughter, Leslie, says she has experienced few side effects and has
felt ''renewed zest just knowing there's something that could potentially
No one expects any of the new biological therapies, as effective as they
may prove, to do the job alone. Most researchers believe they will work
best when combined with other therapies and with standard chemotherapy
drugs to attack the elusive cancer cell on many fronts.
''We don't have to hit a home run to cure people'' with newer agents, says
Dr. Christopher Logothetis at M.D. Anderson. ''We just have to get a base
hit, because we already have one with chemotherapy - this could give us a
run batted in. That's why many of us are really optimistic that we're going
to be able to change the course of this illness.''
For example, ImClone's cancer drug C225, based on an antibody discovery by
Mendelsohn, is being tested in combination with radiation for head and neck
cancers. The radiation damages the cell while the C225 antibody blocks a
chemical growth factor, the EGF receptor, that the cell needs in order to
divide. The one-two attack has proven successful in halting tumors in the
early tests, says Mendelsohn.
If they are cautiously optimistic that the new era of rationally designed
drugs and targeted therapies may yield major inroads into the disease, the
researchers are also mindful of the potential pitfalls.
Normal cells in body tissues are of one kind, but cancer cells - even in
the same tumor - are genetically diverse, points out Coffey at Johns
Hopkins. ''Diversity allows cancer to survive'' by becoming resistant to
drugs that attack just one type of cell, he says. ''Cancer is an
evolutionary process that spins off variants you can't control.''
Angiogenesis inhibitors may get around this obstacle because they don't
attack the cancer cell itself, only its blood supply, and the blood vessel
cells that are the target don't develop resistance. In animal experiments,
resistance to the angiogenesis agents has been remarkably absent.
Hurdles remain before
drugs reach market
But there are other hurdles. Turning experimental proteins from the
laboratory into commercial-scale drugs is difficult. Many of the proteins
are large, complex, and difficult to make. Genentech is building a new
manufacturing plant to churn out a drug called Herceptin for what is
expected to be a large market, once it gains FDA approval. But these
scale-ups take time and effort. Moreover, large proteins need to be taken
intravenously; the hope is to produce small molecules that patients can
Other researchers still labor to find better ways to test promising drugs
in animals. Though scientists have worked for years to create mice that
mimic human cancer, mice experiments still often don't predict what a drug
will do in humans, and the search for still better animal models continues.
Says Dr. Martin Abeloff, director of the Johns Hopkins Cancer Center:
''We're all excited about the potential of really being able to attack this
disease in a more scientifically-based approach. But we also have to be
cautious, because we're learning about the complexity of these processes.''
And, he says, it's not as if cancer treatment is moving into a ''different
''I don't feel like what we've done in the past'' with conventional
treatments will be rendered obsolete, he says. ''We'll never abandon them,
even when we have the new biologically-based approaches... we'll use them
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This story ran on page A01 of the Boston Globe on 08/03/98. Copyright 1998
Globe Newspaper Company.