ROCHESTER, MinnesotaAccurate surrogate markers that would
help researchers predict clinical response to systemic cancer chemotherapy and
greatly speed development of new treatments may be on the way. Alex A. Adjei,
MD, PhD, discussed these anticipated markers that will be much more precise
than those currently in use. Dr. Adjei is consultant in oncology at the Mayo
Clinic in Rochester, Minnesota.
"The ideal surrogate marker would be sensitive and
specific, present in accessible tissue, measurable in a simple assay adaptable
to clinical use, and would correlate with results in tumor tissue," Dr.
Adjei said. Markers might measure pharmacodynamic effects such as topoisomerase
I cleavable complex formation, decreased metabolism (perhaps measured using PET
scans), increased apoptosis, or decreased blood flow/angiogenesis inhibition.
Potential uses of reliable surrogate markers include improving
patient selection for treatment and early prediction of responses in clinical
Identifying New Markers
Appropriate methods for identifying such markers, according to
Dr. Adjei, include proteomics (immunoblotting), immunohistochemistry,
commercially available enzyme inhibition assays, measurements of gene
expression, magnetic resonance imaging (MRI), and functional imaging. "The
problems with previous correlative studies have included use of nonstandardized
methods and arbitrary interpretation of data," he said.
Dr. Adjei discussed the use of estrogen receptor (ER)
expression in breast cancer as an example of these problems. "The key
question is, what is the definition of ER-positivity?" he said.
A survey of a cohort of pathologists by the American College of
Pathology revealed that the definition of estrogen receptor positivity by
immunohistochemistry ranged from any cells staining positive to 50% of cells
‘‘Given these data, it is amazing that we have been as
successful as we have in using ER status as a marker," said Dr. Adjei.
Surrogate FTI Markers
Surrogate markers of farnesyl transferase inhibitor (FTI)
activity have been investigatedfirst, in various human cancer cell lines,
and subsequently in patient tissues, Dr. Adjei noted. Candidates include Ras
expression, p21, and farnesylated proteins. Dr Adjei and his colleagues have
generated antibodies against the prepeptide of prelamin A, which is a substrate
for farnesyl transferase. Prelamin A is farnesylated, and this prepeptide is
cleaved to form mature lamin A. The antibody therefore recognizes
unfarnesylated prelamin A, which is a marker of FT inhibition. The antibody has
been used in immunohistochemical assays to identify FT inhibition in relevant
cells. Unfortunately, the immunohistochemical assay does not work with
formalin-fixed tissue. In addition, lymphocytes do not contain lamin A, so it
would not work as an assay in blood samples. As an alternative, the Mayo Clinic
researchers have tested buccal mucosa cells.
"These cells are well suited for immunohistochemistry and
gene expression studies. There is rapid turnover of the cell population, and
the cells are easily accessible with noninvasive sampling methods," Dr.