BETHESDA, MarylandCell signaling pathways offer many potential
targets for antitumor therapies, but hitting those targets is proving more
difficult than researchers had anticipated, according to John J. Wright, MD,
PhD. He is senior clinical investigator, Investigational Drug Branch, Cancer
Therapy Evaluation Program, at the National Cancer Institute in Bethesda,
"Gleevec (imatinib mesylate) is the paradigm for targeted
therapy and appears to be a therapeutic home run. Unfortunately, identifying
future agents with the efficacy of Gleevec, especially in solid tumors, is
likely to be difficult," Dr. Wright said.
Trials of the EGFR inhibitor Iressa (ZD1839) are a case in
point. "There did not appear to be any difference in efficacy [attributable to
Iressa treatment] in two major clinical trials of NSCLC patients," Dr. Wright
reported. Similarly, adding Avastin (bevacizumab), a monoclonal antibody
targeting angiogenesis, to capecitabine doubled response rates compared to
capecitabine alone but had no effect on overall survival or on time to
progression in a study of patients with breast cancer.
"We are looking again at clinical trial design and considering
changes in endpoints, changes in patient selection criteria, and use of
combinations of targeted therapies," Dr. Wright said. He added, "We are also
concerned about the need to rule out interactions between the targeted agents
Hot New Target
Biological context is also a consideration. The proteasome
emerged last year as a hot new target for anticancer treatments but is also
required for maintaining normal cell functions. "Preclinical studies suggest
that a baseline of at least 20% proteasome activity is needed for housekeeping
functions. If inhibition is greater than that, and particularly if inhibition
is prolonged, you cause significant morbidity and mortality," Dr. Wright said.
The proteasome inhibitor PS-341 overrides a common mechanism of
chemoresistance. Dr. Wright said that PS-341 has significant synergy with
irinotecan, with radiotherapy, and with various other chemotherapeutic agents.
"PS-341 has a short half-life that cannot yet be measured by
conventional pharmacokinetics, so it was necessary to develop an assay of the
effect on proteasome activity in blood cells," he explained. Phase I trials
showed good correlation between this pharmacodynamic assay and PS-341 dose.
The histone deacetylase inhibitor depsipeptide (FK-228) is in
phase II trials in T-cell lymphomas, reflecting new awareness of the importance
of chromatin modulation for regulating gene expression. Dr. Wright said that
cardiotoxicity in preclinical studies delayed development of this compound, but
NCI toxicologists identified administration schedules to reduce toxicity.
There is considerable interest, based on encouraging
preclinical data, to combine HDAC inhibitors like depsipeptide with
hypomethylating agents (decitabine) to maximize the gene expression effects of
both compounds. Preliminary phase I studies of these combinations are in
progress, sponsored by CTEP.