continuing search for surrogate markers
for testing new anticancer drugs
received a critical update at a scientific
symposium at ASCO on "Early Indicators
of Clinical Effect. Do Targeted
Therapies Hit Their Targets?"
New concepts in assessing inhibitors
of epidermal growth factor receptor
(EGFR) signal transduction infailure
clude pharmacodynamics, pharma-
cogenomics, and pharmacodiagnostics,
according to Manuel Hidalgo,
MD, of Johns Hopkins Medical Center
in Baltimore. "But inhibition of a
molecular target is not the same as an
antitumor effect," he cautioned.
Effects on target markers are especially
important if early studies do not
show objective tumor responses. The
to inhibit tumor growth might
be a sign of inadequate dosing, he said.
Failure to inhibit the target indicates
that a new drug is needed. Failure to
inhibit tumor growth despite inhibiting
the target marker means that a new
target marker or a combination of dif-
ferent agents is needed.
Dr. Hidalgo emphasized the critical
need for validated surrogate tissue
markers for pharmacodynamic studies
that could be used in large clinical
trials. "We can't do the studies needed
in phase II trials using tumor tissue
because it is not feasible to do paired
tumor biopsies in hundreds of patients.
We need validated surrogates
to use early after treatment to predict
which patients will do well," he said.
"The traditional divergence between
diagnostic and therapeutic
groups must be transcended in order
for biomarker research to be more
supported and better integrated into
therapeutics development," noted
John W. Park, MD, of the University
of California, San Francisco. He emphasized
that biomarkers should be
defined in advance and applied
throughout the development process.
Pathway as Paradigm
Alex A. Adjei, MD, PhD, of the
Mayo Clinic, Rochester, Minnesota,
used the ras-MAP-kinase pathway as a
paradigm for discussing aspects of targeted
therapy in non-small-cell lung
cancer (NSCLC). Distinguishing between
biomarkers and surrogate markers
is important, he noted. Biomark-
ers are objectively measured and used
to evaluate biological processes. Surrogate
markers are accurate measures
of drug effects but may not measure
the effect on the drug target. "Surrogate
markers can be biomarkers, but
biomarkers are not necessarily surrogate
markers," Dr. Adjei said.
Major uses of biomarkers include
pharmacodynamic markers, response
prediction, and patient selection.
Pharmacodynamic markers show that
the drug inhibits the target, and, they
are useful in phase I trials. They can be
used with surrogate tissues, although
tumor tissue is preferable. "In most
cases, surrogate tissue is inappropriate
for phase II trials unless you can
show that the effect is the same as what
would happen in the tumor. The target
must be critical for the activity of
the drug," he added.
Markers for response prediction
might include negative predictors to
exclude patients who will not respond
to the therapy.
For markers used for patient selection,
such as HER2/neu or EGFR, tumor
samples are key, according to Dr.
Adjei. "The target must be critical for
the action of the drug, and the assay
must be validated," he stressed. "Don't
forget the pharmacology: what does
the host do to the drug? Markers must
be validated. The take-home message
is that you must do your homework
before you start a clinical trial."
Discovery of Differences
David Carbone, MD, PhD, of
Vanderbilt University Medical Center,
Nashville, Tennessee, discussed
tumor proteomics in targeted therapy,
particularly with regard to lung
cancer. "Lung cancer survival is really
poor, and we don't have very good
treatments," he said. "The number of
cases each year is almost the same as
the number of deaths."
The search for molecular signatures
is currently a hot area in lung cancer
research. "We all believe that there are
some properties of cancers that determine
why one patient responds and
another does not; why one patient is
cured and another isn't; why one patient
has metastases and another does
not," Dr. Carbone said.
The discovery of differences related
to mutations in the EGFR is "the
most important finding in the genetics
of lung cancer," he said. However,
some responders and patients who
develop stable disease in response to
EGFR inhibitors do not have the identified
EGFR mutations, and some who
do are resistant to EGFR inhibitors
such as gefitinib (Iressa). "Our hypothesis
is that this is a complex phenotype
that can be predicted by analysis
of complex gene/protein patterns,"
Researchers have already found that
metastatic potential is encoded in the
bulk of the primary tumor rather than
in subclones within the tumor and that
many solid tumors have gene/protein
patterns similar across tumor types.
"The name of the game is clinical
benefit. It would be nice to have pre
of clinical benefit, not just of
super-responders," Dr. Carbone said.
Proteomics is important because
most nucleic acid sequences exert their
effect on translation. "Activity comes
from the protein, not the gene," Dr.
One method that can be used for
proteomic profiling and requires only
a few cells is matrix-assisted laser desorption/
ionizing mass spectrometry
(MALDI). Dr. Carbone said that MALDI
analysis has already identified protein
profiles associated with improved
survival in lung cancer.
"MALDI uses frozen samples of
tumor and requires no processing or
extraction. It can distinguish primary
from metastatic tumor and can detect
mediastinal lymph node involvement,
which has major implications for management
of lung cancer. This could
potentially improve lung cancer outcomes.
We have found a 15-protein
pattern that predicts prognosis in lung
cancer and might be useful for identifying
patients for further therapy."
Dr. Carbone also described the use
of MALDI in nonsurgical samples. The
method was 99% specific at detecting
bronchial preneoplastic changes in preliminary
studies. "Each MALDI test
costs only a couple of dollars to perform,
once you buy the million-dollar
machine," he added
The downside is that MALDI can
be performed only on small proteins,
and formalin-fixed tissues cannot be