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Efforts Continue to Uncover Early Indicators of Clinical Effect

Efforts Continue to Uncover Early Indicators of Clinical Effect

NEW ORLEANS-The continuing search for surrogate markers for testing new anticancer drugs received a critical update at a scientific symposium at ASCO on "Early Indicators of Clinical Effect. Do Targeted Therapies Hit Their Targets?" New concepts in assessing inhibitors of epidermal growth factor receptor (EGFR) signal transduction infailure clude pharmacodynamics, pharma- cogenomics, and pharmacodiagnostics, according to Manuel Hidalgo, MD, of Johns Hopkins Medical Center in Baltimore. "But inhibition of a molecular target is not the same as an antitumor effect," he cautioned. Effects on target markers are especially important if early studies do not show objective tumor responses. The failure to inhibit tumor growth might be a sign of inadequate dosing, he said. Failure to inhibit the target indicates that a new drug is needed. Failure to inhibit tumor growth despite inhibiting the target marker means that a new target marker or a combination of dif- ferent agents is needed. Dr. Hidalgo emphasized the critical need for validated surrogate tissue markers for pharmacodynamic studies that could be used in large clinical trials. "We can't do the studies needed in phase II trials using tumor tissue because it is not feasible to do paired tumor biopsies in hundreds of patients. We need validated surrogates to use early after treatment to predict which patients will do well," he said. "The traditional divergence between diagnostic and therapeutic groups must be transcended in order for biomarker research to be more supported and better integrated into therapeutics development," noted John W. Park, MD, of the University of California, San Francisco. He emphasized that biomarkers should be defined in advance and applied throughout the development process. Pathway as Paradigm Alex A. Adjei, MD, PhD, of the Mayo Clinic, Rochester, Minnesota, used the ras-MAP-kinase pathway as a paradigm for discussing aspects of targeted therapy in non-small-cell lung cancer (NSCLC). Distinguishing between biomarkers and surrogate markers is important, he noted. Biomark- ers are objectively measured and used to evaluate biological processes. Surrogate markers are accurate measures of drug effects but may not measure the effect on the drug target. "Surrogate markers can be biomarkers, but biomarkers are not necessarily surrogate markers," Dr. Adjei said. Major uses of biomarkers include pharmacodynamic markers, response prediction, and patient selection. Pharmacodynamic markers show that the drug inhibits the target, and, they are useful in phase I trials. They can be used with surrogate tissues, although tumor tissue is preferable. "In most cases, surrogate tissue is inappropriate for phase II trials unless you can show that the effect is the same as what would happen in the tumor. The target must be critical for the activity of the drug," he added. Markers for response prediction might include negative predictors to exclude patients who will not respond to the therapy. For markers used for patient selection, such as HER2/neu or EGFR, tumor samples are key, according to Dr. Adjei. "The target must be critical for the action of the drug, and the assay must be validated," he stressed. "Don't forget the pharmacology: what does the host do to the drug? Markers must be validated. The take-home message is that you must do your homework before you start a clinical trial." Discovery of Differences David Carbone, MD, PhD, of Vanderbilt University Medical Center, Nashville, Tennessee, discussed tumor proteomics in targeted therapy, particularly with regard to lung cancer. "Lung cancer survival is really poor, and we don't have very good treatments," he said. "The number of cases each year is almost the same as the number of deaths." The search for molecular signatures is currently a hot area in lung cancer research. "We all believe that there are some properties of cancers that determine why one patient responds and another does not; why one patient is cured and another isn't; why one patient has metastases and another does not," Dr. Carbone said. The discovery of differences related to mutations in the EGFR is "the most important finding in the genetics of lung cancer," he said. However, some responders and patients who develop stable disease in response to EGFR inhibitors do not have the identified EGFR mutations, and some who do are resistant to EGFR inhibitors such as gefitinib (Iressa). "Our hypothesis is that this is a complex phenotype that can be predicted by analysis of complex gene/protein patterns," he said. Researchers have already found that metastatic potential is encoded in the bulk of the primary tumor rather than in subclones within the tumor and that many solid tumors have gene/protein patterns similar across tumor types. "The name of the game is clinical benefit. It would be nice to have pre predictors of clinical benefit, not just of super-responders," Dr. Carbone said. Proteomic Profiling Proteomics is important because most nucleic acid sequences exert their effect on translation. "Activity comes from the protein, not the gene," Dr. Carbone said. One method that can be used for proteomic profiling and requires only a few cells is matrix-assisted laser desorption/ ionizing mass spectrometry (MALDI). Dr. Carbone said that MALDI analysis has already identified protein profiles associated with improved survival in lung cancer. "MALDI uses frozen samples of tumor and requires no processing or extraction. It can distinguish primary from metastatic tumor and can detect mediastinal lymph node involvement, which has major implications for management of lung cancer. This could potentially improve lung cancer outcomes. We have found a 15-protein pattern that predicts prognosis in lung cancer and might be useful for identifying patients for further therapy." Dr. Carbone also described the use of MALDI in nonsurgical samples. The method was 99% specific at detecting bronchial preneoplastic changes in preliminary studies. "Each MALDI test costs only a couple of dollars to perform, once you buy the million-dollar machine," he added The downside is that MALDI can be performed only on small proteins, and formalin-fixed tissues cannot be used.

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