More on the difficulty in designing "targeted therapy" cancer drugs.
Researcher's thinking seems to be moving away from "one size fits
all" therapy (as things are currently done), towards creating
personalized therapy based on each patients' genetic tumor profile:

[snip]
At best, experts now expect knocking down cancer will require an
elaborate mixture of targeted drugs, assembled to match the distinct
biology of each person's cancer.
"It's a much more complicated problem than anyone ever appreciated,"
said Dr. Leonard Saltz, a colon cancer expert at Memorial Sloan-
Kettering Cancer Center. "It will, unfortunately, be with us for a
long time."

*********************************************************************
New Drugs for Cancer Give Hope, Not Cure
InsideVC.com
Daniel Q. Haney, AP medical editor
July 27, 2003



Not long ago, the defeat of cancer seemed inevitable. Decades of
research would soon pay off with a completely fresh approach, an
arsenal of clever new drugs to attack the very forces that make
tumors grow and spread and kill.

No more chemotherapy, the thinking went. No more horrid side effects.
Just brilliantly designed drugs that stop cancer while leaving
everything else untouched.

Those elegant drugs are now here. But so is cancer.

The approach, which appeared so straightforward, has proven
disappointingly difficult to turn into broadly useful treatments.
Some now wonder if malignancy will ever be reliably and predictably
cured.

The dearth of substantial impact so far suggests the fight against
cancer will continue to be a tedious slog, and victories will be
scored in weeks or months of extra life, not years. The full
potential of the new approach may take decades to be realized.

The drugs, called targeted therapies, are intended to arrest cancer
by disrupting the internal signals that fuel its unruly growth.
Unlike chemo, which attacks all dividing cells, these medicines are
crafted with pinpoint accuracy to go after the genetically controlled
irregularities that make cancer unique.

Several have made it through testing, but despite their apparent
bull's-eye hits, lasting results are rare. Instead, these new drugs
turn out to be about as effective -- or as powerless -- as old-line
chemotherapy. Aimed at the major forms of cancer, they work
spectacularly for a lucky few and modestly for some.

But for most? Not at all.

Resilient enemy

Doctors have many theories about what's gone wrong. But it is clear
that cancer is a surprisingly robust foe, packed with convoluted
backup systems that kick in when threatened by the new drugs.

At best, experts now expect knocking down cancer will require an
elaborate mixture of targeted drugs, assembled to match the distinct
biology of each person's cancer.

"It's a much more complicated problem than anyone ever appreciated,"
said Dr. Leonard Saltz, a colon cancer expert at Memorial Sloan-
Kettering Cancer Center. "It will, unfortunately, be with us for a
long time."

The job is so daunting, especially for advanced cancers propelled by
potentially dozens of nefarious genetic mutations, that scientists
are even rethinking the goal of cancer research.

"Society as a whole, and most of the medical profession, have it
wrong, understanding we'll wake up one morning and find out cancer is
cured. It won't happen. The public should give it up," said Dr. Craig
Henderson, a breast cancer specialist at the University of
California, San Francisco, and president of Access Oncology, a drug
developer.

"What we have learned by these billions of dollars invested in cancer
biology is that cancer are us," he goes on. True, cancer is
different. But not different enough. "Identify what makes cancer
unique and wipe it out? That won't happen. We cannot wipe out the
cancer without wiping out a lot of the rest of us."

Henderson and many others have shifted their sights to something
less -- converting cancer into a chronic disease, like diabetes or
AIDS. Treatments might slow or even stop its worst effects so people
survive for years reasonably free of symptoms.

Dr. Andrew von Eschenbach, head of the National Cancer Institute,
argues that a cure is not even necessary if this can be done,
something he optimistically hopes to see by 2015. But eliminate
cancer? "Not in the foreseeable future," he said.

Still, experts concede there is no firm evidence that targeted
treatments will tame cancer to a chronic condition, either.
Certainly, the ones tested so far do not often come close to this for
the common varieties, such as lung, breast, colon and prostate
cancer.

Euphoria over Herceptin

Although targeted therapies have their origins in basic cancer
discoveries of the 1980s, the story for many began at a meeting of
the American Society of Clinical Oncology in 1998. Researchers were
thrilled to hear of the first convincing demonstration that a
targeted drug could slow the course of cancer even a little. It was
proof that the principle is sound.

Usually wary oncologists rhapsodized about a new era of treatment. "A
tidal wave," one of them called it. Even then, no one predicted quick
cures. But they clearly felt they at least had the key to getting
inside cancer and fixing it.

The drug that caused the euphoria, Herceptin, became a standard
treatment for spreading breast cancer, typically delaying progression
by a few months in the quarter of victims with a particular genetic
profile.

Since Herceptin, targeted drugs have become the prevailing approach
in cancer research. Whenever any of these make slight progress, the
news is widely and sometimes breathlessly reported. An estimated two-
thirds of the nearly 400 cancer medicines in human study take this
tack. Yet researchers do not envision successes any more spectacular
from this pipeline than the modest effects of the handful already on
the market.

"Right now, in the short run, we can bring an occasional miracle and
have an overall small benefit," said Dr. John Glaspy, medical
director of UCLA's surgical oncology center. "But there has not been
a major improvement on what happens to them ultimately."

Furthermore, the dream of abandoning chemotherapy has largely
evaporated. Even the targeted drugs' small benefits are typically
seen only when combined with standard chemo.

Cancer doctors facing waiting rooms full of dying cancer patients,
with little to offer but easing misery and perhaps a few extra months
of survival, clearly had wished for more.

"The hope was that these targeted therapies would be the new magic
bullet and would cure cancer," said Dr. David Decker, an oncologist
at William Beaumont Hospital outside Detroit. "It's fair to say they
haven't panned out the way we thought they would."

Drugs offer reprieve

The targeted drugs have been most impressive against cancers of the
blood and immune system, which are easier to control than the more
common organ tumors. For instance, about half of patients getting
Rituxan for non-Hodgkin's lymphoma have at least a 50 percent
reduction in their cancer, and the improvement lasts an average of a
year before the disease progresses again.

The one striking success, Gleevec, unfortunately works only against
two rare blood and digestive cancers that involve unusually simple
signaling pathways, offering ideal targets. Even so, Gleevec's
stunning effects -- close to 90 percent initially get better -- often
wear off in time.

In 2001, Dean Gordanier, a Boston tax attorney with a cancer-swollen
belly, was "pretty much dying" when he started on Gleevec. For 18
months, it was a miracle. He gained weight and went back to work.
Then, the day before Christmas, he learned the tumor was growing
again.

For most who win a cancer reprieve, that would be the end. But as it
turned out, another experimental targeted drug was available at the
Dana Farber Cancer Institute, and Gordanier's cancer is in retreat
again, although he expects this medicine, too, will eventually fail.

"I feel like I'm riding the crest of a wave," he said. "It could dump
me at any time, but right now I'm cruising."

Dr. Brian Druker of Oregon Health and Sciences University, one of
Gleevec's developers, said, "What Gleevec tells us is if we have the
right target and the right drug, we will have spectacular results.
Until then, we will be mired in incremental gains."

Scant success

Those gains seem especially incremental against the far more
complicated common cancers. For instance, the drug Iressa was
approved in May on evidence that it temporarily shrinks advanced lung
cancer in just 10 percent of patients. Doctors often assume drugs
will work better if given earlier in the disease. But when Iressa was
combined with chemotherapy in newly diagnosed lung cancer, the
patients did not respond to it at all.

Others in the pipeline seem hardly more potent.

At this June's clinical oncology meeting, doctors reported the
results with two targeted drugs for advanced colon cancer: A growth
signal blocker called Erbitux (the same medicine that ensnarled
Martha Stewart in a Wall Street scandal) temporarily shrank tumors in
a quarter of patients. And Avastin, intended to stop cancers from
building blood vessels, improved average survival by four months.

In theory, all of these drugs should work better, because they block
the communication pathways hijacked by the genetic mutations that
become cancer.

Cancer occurs when five to 10 ordinary genes develop mutations in a
single cell over a person's lifetime, the consequence of biological
insults like smoking or just bad luck. As a result, the genes may get
stuck in hyperdrive, churning out huge amounts of growth-stimulating
proteins, or perhaps they get turned off inappropriately, robbing
cells of their brakes. Whatever the problem, the result is cells that
divide over and over, that take root in parts of the body where they
don't belong, that lose the normal instinct to self-destruct when
their wiring goes awry and that simply never die.

This mess is fueled by hundreds, even thousands, of individual
proteins. The process of making new blood vessels alone may entail 30
or 40 of them lined up in several signaling pathways.

Doctors still hopeful

With targeted drugs, scientists envisioned bringing the entire
process to a halt by chemically knocking out a single protein link in
one chain of communication. Like a cut phone line, no signal gets
through. Therefore, no more growth and no new cancer.

Although the process has not worked out to be this simple, many in
the field believe that eventual progress is likely. Maybe the best-
case scenario is spun out by the Dana Farber's Dr. William Kaelin. He
theorizes that a few key pathways will prove important in many kinds
of cancer, and drugs will be created to effectively block them.

Several dozen drugs may offer enough choices to cover all the typical
genetic combinations at work in cancer. "This is the belief that is
driving all of us," said Kaelin. With the right mix of three or four
drugs for any individual, "We will make a major inroad into the
common adult tumors, such as lung, colon and breast cancer."

Though they hoped for more, many cancer specialists seem relieved for
now to have anything new to offer at all. Even small advances are
welcome in a profession where progress often seems glacial.

"It is slower progress than we'd like, but that's the nature of
medicine," said Dr. Donald Trump, chairman of medicine at Roswell
Park Cancer Institute in Buffalo, N.Y. "A disease process as complex
as cancer is unlikely to yield to blockbuster effects."