Molecularly
Targeted Therapy:
Residual Cancer Cells Find Their Way Around
November / December 2005
Enthusiasm for molecularly targeted therapies, which serve
as a major focus for current cancer drug development efforts,
needs to be tempered by the realities of cancer therapy,
namely that tumors tend to become resistant to drugs, according
to Lewis A. Chodosh, MD, PhD, Director of Cancer Genetics
at the Abramson
Family Cancer Research Institute of the University of
Pennsylvania.
Recent spectacular successes in treating certain cancers
with a select group of molecularly targeted therapies has
prompted a frenzy of research into this class of drugs as
well as a great deal of excitement within the oncology community.
Similarly, surprising recent experimental findings suggested
that single molecular targeted agents were sufficient to
cure cancer in mice.
After designing an experiment with genetically engineered
mouse models for breast cancer to address this issue, Dr.
Chodosh and colleagues demonstrated that – as in human
patients – small numbers of cancer cells do indeed
remain following targeted therapy and provide the means for
cancers to escape and eventually recur.
“What this means for cancer treatment today is that
the molecularly targeted therapies that are coming on board
and that are in clinical trials will almost certainly need
to be considered as agents that must be used in combination
in order to be maximally effective,” said Dr. Chodosh. “There
simply won’t be many drugs that are going to cure cancer
by themselves.”
The first molecularly targeted drug to show such promise
was imatinib mesylate (Gleevec®), which produces remarkable
response in patients with chronic myelogenous leukemia as
well as certain other cancers, and has very few side effects
compared to chemotherapy. This turned the attention of researchers
in general and the pharmaceutical industry in particular
toward finding a ‘silver bullet’ to target critical
genetic pathways fo each type of cancer, according to Dr.
Chodosh.
Results of animal models based on this theory suggested
that not only would turning off an oncogenic pathway be highly
efficacious, but that doing so could be a cure for cancer.
Further, Dr. Chodosh pointed out these findings
suggested that oncogenic pathways needed only to be turned
off briefly in order to have long-lasting effects.
“The suggestion was that all you have to do is treat
patients briefly with molecularly targeted agents and they’ll
be cured,” explained Dr. Chodosh. “More surprising
still, it has been reported that if the oncogene gets turned
on again in those residual cells that remain (akin to terminating
therapy with a molecularly targeted agent) such cells are
resistant to becoming cancerous.”
Dr. Chodosh and colleagues performed a study to test that
theory in the context of breast cancer because, he said, “our
feeling, as physicians, was that this represented a not very
realistic view of cancer as it is seen in the clinic where ‘escape’ is
the rule of the day. We thought that molecularly targeted
drugs might indeed result in the death of most of the cells
within a cancer, and might even stop the remaining cells
from dividing for a time, but that the likelihood was, just
as with conventional therapies, that cancer cells would ultimately
escape.”
Dr. Chodosh and colleagues used a mouse model of breast
cancer in which they turned off the gene c-MYC, which is
commonly overexpressed in human breast cancer. Turning off
the gene simulates the effect of blocking the oncogene pathway.
“What we found was something much more familiar to
clinicians,” said Dr. Chodosh, “Namely, though
turning off c-MYC results in dramatic tumor regression in
many cases, some residual neoplastic cells almost always
remain at the end of the process.” Dr. Chodosh explained
that the data suggests that if you block a dominant oncogenic
pathway with a molecularly targeted agent, it may well be
effective, but it won’t be sufficient to cure a patient
with an epithelial tumor due to the tendency of remaining
tumor cells to escape by some other pathway.
“In addition, when we turned c-MYC back on, we found
that – contrary to the cells being resistant to oncogene
reactivation as the provocative research had suggested – the
residual tumor cells actually remained exquisitely sensitive
to it. When we turned c-MYC back on in these animals, they
had tumors again within a few days,” said Dr. Chodosh.
Molecular therapies will likely need to be applied chronically
to prevent the re-growth of residual tumor cells that
remain after therapy, according to Dr. Chodosh. He further
emphasizes that molecularly targeted therapies will need
to be combined with agents that target secondary pathways
of tumor escape to achieve lasting results.
“Any way you look at it,” he said, “when
physicians apply a selective pressure to a tumor by blocking
an oncogenic pathway, cells escape. They find a back door
and progress to a more aggressive state that becomes independent
of that pathway.”
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