WASHINGTONThe ongoing revolution in knowledge about the
cellular processes that lead to cancer has created a new and
potentially far more efficient approach to finding effective
therapeutic agents, said Edward A. Sausville, MD, PhD, associate
director of the NCIs Developmental Therapeutics Program.
Speaking at a symposium at the Annual Meeting of the American
Association for the Advancement of Science (AAAS), Dr. Sausville
contrasted the old, inefficient empirical approach of
screening and testing candidate drugs with the new approach based on
Traditionally, Dr. Sausville said, screening compounds for anticancer
potential has focused on seeking signs of anticancer activity,
specifically the ability to shrink tumors. This research model has
poor predictive power because of the poor correlation between
agents efficacy in animal models and in humans, he said.
In some cancer models, such as breast, the traditional screening
process has been very unreliable in predicting clinical
results, he said, while in others, such as non-small-cell lung
cancer, it has been somewhat more predictive, but has not
produced striking results, he added.
The New Approach
The new approach to drug development targets therapeutic agents
against specific cancer-related processes within the cells. The goal
is to identify molecules that can be critically directed at the
processes that actually drive neoplasms, Dr. Sausville said.
Such a process will reveal clinical usefulness much earlier in the
development process, he said.
The bcr-abl fusion protein, for example, is known to be
expressed in certain leukemias, he said. It acts as a kinase
mediating cellular growth in these neoplasms but not in normal cells.
Two generations of synthetic drug development have produced STI 571,
a protein that has shown activity in mice and also has produced
promising human data in phase I trials in chronic myelogenous
leukemia, Dr. Sausville said.
Todays understanding of cell mechanisms provides a rich
tapestry of other targets, Dr. Sausville remarked. Onco-genes,
such as ras, for example, appear in mutated form in a large
percentage of cancers, including 90% of breast cancers and 40% to 60%
of various other cancers. A number of potential inhibitors have been
identified, he said, although it is as yet unclear whether any will
show the desired specificity against this oncogene.
Such abnormal gene expression serves as the fingerprint
of cancer cells, he said, and can show researchers where to look for
molecular targets within cancer cells. Neuroblastoma, for example,
shows a genetic difference that might serve as a useful target, he noted.
The fact that molecular patterns of activity unique to cancer cells
are now known to cut across cell types makes it possible to select
drugs with specific activities and target them at appropriate
cellular molecules, he said. Algorithms that compare the molecular
patterns of activity of standard agents are helping to define
categories of compounds according to their action. Such information
also provides insight into how to build molecules to attack specific
Dr. Sausville predicted that genetic libraries (see box ) will allow
researchers to assess compounds according to the molecular structure
of their targets. By the time these candidate compounds enter
clinical trials, their likelihood of acting within human cancer cells
will already be clear.
The CGAP Project
To help streamline and generalize the process of searching for
These are rapidly being placed in the public domain on a CGAP
This genetic library will become a tremendously interesting and
This new approach to drug development will also open the way for
reassessing and improving compounds studied in the past, he said.