The principal goal of this application by a group of molecular and clinical pharmacologists, molecular biologists, and clinical scientists from the California Cancer Consortium (CCC) comprised of three NCI-designated Cancer Centers 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 (COM), 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 10,000 new cancer patients per year), a strong record of accrual to Phase I and Phase ll-lll cancer clinical trials (over 1250 total patient accessions in 2006), and a history of productive clinical research interactions among the three institutions (over 2000 patients entered on joint Phase I and II studies). 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 genetic or epigenetic abnormalities in cancer cells; 2) agents that target signal transduction pathways, the cell cycle, and host/tumor interactions; 3) agents that are potentially active in hematologic malignancies; 4) agents developed through CCC investigator-initiated RAID projects; and additionally, 5) to examine in special patient populations the clinical pharmacology of targeted anticancer agents whose therapeutic effects may be altered because of abnormal organ function or because of inherited differences in genes controlling drug disposition and activity; and 6) to identify new and informative laboratory correlates of biologic activity and drug resistance and explore novel functional endpoints of tumor response, progression, and clinical benefit for patients entered on the Phase I clinical trials of the CCC. ? ? ?
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