Developing Targeted Therapy More Difficult Than Anticipated

BETHESDA, Maryland—Cell 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, Maryland.

"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 and chemotherapy."

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.

Chromatin Modulation

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.