The principal goal of this proposal by a group of molecular and clinical pharmacologists, molecular biologists, and clinical scientists from a consortium comprised of two NCI-designated Comprehensive Cancer Centers and a large University Hospital is to develop new, laboratory-based cancer treatment strategies for application in the early therapeutic trial setting. These Phase I studies will lead not only to the assignment of a recommended, biologically effective Phase II dose, and to an understanding of the spectrum of normal tissue toxicity for specific antineoplastic agents that are directed against novel molecular pathways, but will also provide a mechanistic validation of the effects of the agents on critical tumor cell targets, correlate drug-related alterations of tumor and host biologic markers with clinical outcome, and develop new insights into the therapeutic mechanism of action of Phase I compounds both in the laboratory and the clinic. The investigational methodologies to be used are based on specific areas of scientific and clinical research expertise available at the City of Hope Comprehensive Cancer Center (COH), the University of Southern California (USC)/Norris Comprehensive Cancer Center, and the University of California, Davis Cancer Center (UCD). The Phase I trials to be pursued will be supported by the availability of a large patient resource (in excess of 7000 new cancer patients per year), a strong record of accrual to Phase I and Pilot/Phase I-II cancer clinical trials (over 320 total patient accessions in 2001), and a history of productive clinical research interactions among the three institutions (over 1500 patients entered on joint Phase I and II studies over the past seven years). We propose to utilize the combined expertise of COH, USC, and UCD in the areas of molecular pharmacology, pharmacokinetics, pharmacodynamics, pharmacogenomics, signal transduction, cell cycle regulation, non-invasive imaging, and bioinformatics to conduct innovative, laboratory-directed Phase I developmental and pharmacokinetic studies supported by CTEP, NCI that focus on: 1) agents that target specific genetic or epigenetic abnormalities in cancer cells as their unique antineoplastic mechanism of action or toxicity; 2) the examination in special patient populations of the clinical pharmacology of targeted cancer therapeutic agents whose disposition may be altered because of abnormal organ function or performance status, or because of genetic polymorphisms that affect anticancer drug action or toxicity; 3) the validation of novel functional endpoints of tumor response, progression or clinical benefit; and 4) the identification of new and informative laboratory correlates of therapeutic activity or resistance that can be applied in the early therapeutic trials of the COH-USC-UCD Consortium.
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