By Gwen Ericson

April 19, 2006 -- The results of a new study at Washington University
School of Medicine in St. Louis could eventually have oncologists
removing their specialties from their shingles by making therapy based
on a tumor's anatomical location obsolete.

When the researchers compared eight different kinds of cancerous tumors,
they saw that whether the tumor was, for instance, a breast tumor, lung
tumor or colon tumor didn't correlate to how the cancers interacted with
a standard anticancer drug.

Their findings suggest that traditional cancer treatments; which have
established different drug regimens for brain, prostate or ovarian
cancer, for example — should eventually be replaced with therapies
that use drugs deemed to be of highest benefit based on the tumor's
pharmacologic profile.

Treatment choice would be determined by how each patient's tumor reacts
to anticancer drugs, regardless of the tumor's anatomical origin.

"This study is the first time the pathway for a drug's effect has been
analyzed in tumors from different anatomical locations," says Howard
McLeod, Pharm.D., director of the pharmacology core at the Siteman
Cancer Center and a member of the National Institutes of Health (NIH)
Pharmacogenetics Research Network.

"We've shown that drug effect is independent of where the tumor came
from in the body. If further studies confirm that a tumor-specific
approach is better than the current anatomical emphasis, oncologists may
have to stop thinking of themselves as colon cancer or breast cancer
specialists and let the cancer tell them which drugs to use for each
specific patient."

The research team analyzed 255 samples of eight different cancers
— colon, breast, prostate, ovary, lung, brain, melanoma and
lymphoma — and measured the amounts of specific proteins known to
influence the effect of irinotecan, a commonly used anticancer agent.
Their study will appear in an upcoming issue of the Journal of
Pathology.

The protein levels that determine irinotecan's effectiveness were found
to be independent of the anatomical origin of the tumor. So, for
instance, the colon tumors studied varied widely in the levels of these
proteins. The same variation in protein levels held true for all of the
tumor types the researchers examined.

"This study provides evidence that the pharmacological pathway of a drug
is important, with significant treatment implications," says Rochelle M.
Long, Ph.D., of the National Institute of General Medical Sciences and
program director for the NIH Pharmacogenetics Research Network. "This
work is in keeping with an overarching Network theme of selecting
therapies tailored for individual patients instead of a
one-size-fits-all approach."

The researchers found that, independent of anatomical origin, some
tumors had high amounts of irinotecan's cellular target, a protein
labeled TOP1, while other tumors had very little. Irinotecan would
likely be ineffective in tumors with low TOP1 levels. They also found
that tumors varied greatly in the amounts of proteins that transport
irinotecan into and out of their cells and in the amounts of proteins
that break down irinotecan.

These variations determine how well irinotecan will work in a particular
tumor.
"Because tumor response can't be predicted from anatomical location, we
should start selecting treatments based on what genes and proteins can
tell us about how the tumor will respond to a drug," says McLeod,
professor of medicine, of genetics, and of molecular biology and
pharmacology. "If we rely just on what has clinically been shown to work
in some cases for a particular anatomically defined cancer, we may not
initially choose the best therapy for the individual patient. And with
advanced cancer, a patient may get only one shot at the right therapy
— making the wrong choice could be deadly."

According to McLeod, under current treatment selection methods virtually
no chemotherapeutic drug has been successful in more than 50 percent of
patients with advanced cancer. But instead of considering a drug that
works only ten percent of the time a failure, he feels it would be
better to consider such a drug effective for one in ten tumors and to
search for the agents among the current arsenal of chemotherapeutic
drugs that will work for the rest.

"We have more than 70 FDA-approved drugs that potentially could be
useful for a particular tumor," McLeod says. "We are now working on
methods that can be used to identify those drugs that will work for each
patient's tumor."
Having a good tumor-drug match not only would improve survival rates, it
would be cost-effective, according to McLeod.
"Since modern cancer therapies can be expensive — sometimes
approaching the cost of a bone marrow transplant — the high cost
reinforces the necessity of choosing the right therapy the first time,"
he says.
Funding from the National Institutes of Health supported this research.
 
==========

ABSTRACT of the Article behind this news story:
Zhang W, Shannon WD, Duncan J, Scheffer GL, Scheper RJ, McLeod HL.
Expression of drug pathway proteins is independent of tumor type.
Journal of Pathology, Published Online: 28 Feb 2006.
Departments of Medicine, Pharmacology, Biostatistics, and Genetics, and
the Siteman Cancer Center, Washington University School of Medicine, St
Louis, USA.
Current clinicopathological staging systems have the advantage of
standardized criteria for assessing tumour stage, and a relationship
between advancing tumour stage and poor prognosis has been established
for most cancers. However, these tools have not led to clear criteria
for therapy selection in individual patients. Indeed, the concept of
therapy based on anatomical location seems quaint.
Therefore, a representative drug pathway (irinotecan) was evaluated
across common tumour types to test the hypothesis that pharmacological
proteins are expressed independent of anatomical location.
Many enzymes are involved in controlling the disposition of irinotecan,
including the cellular target (TOP1), metabolism enzymes (CES2, UGT1A1,
CYP3A4, CYP3A5), and cellular transporters of the anti-cancer agent
(ABCB1, ABCC1, ABCC2, ABCC3, ABCC5, ABCG2). These 11 proteins were
evaluated in tissue microarrays containing colon, breast, prostate,
ovary, and lung cancers; brain tumours; melanoma; lymphoma; and selected
normal tissues.
A total of 255 tumours and 37 normal tissue samples were evaluable for
all proteins. Linear discriminant analysis designed to predict the
tissue type from the protein expression levels revealed a 49.6%
misclassification rate, indicating that protein expression of this drug
pathway is not associated with tissue type.
Cluster analysis identified a variety of tumours with the same
pharmacological profile. The anatomy independence of drug pathways
stimulates efforts to move away from our traditional approaches to the
selection of cancer therapy.

 
Siteman Cancer Center is the only NCI-designated Comprehensive Cancer
Center within a 200-mile radius of St. Louis. Siteman Cancer Center is
composed of the combined cancer research and treatment programs of
Barnes-Jewish Hospital and Washington University School of Medicine.
Source: Washington University in St. Louis

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