NEW INVESTIGATOR TRAINING IN DRUG DEVELOPMENT

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DESCRIPTION: (Applicant's Description) The principal purpose of this proposal is to provide salary support for Dr. Spriggs and his career development activities in the area of patient oriented research. Dr. Spriggs currently mentors four young faculty members as well as three medical oncology fellow. He also has direct responsibility for one Gyn Fellow annually. The experimental hypothesis of Dr. Spriggs' own research research program is that drug resistance is controlled by regulation of gene expression. The transciptional regulation of resistance is based on data demonstrating the activation of NF-kB DNA binding is a common feature of acquired CDDP resistance in ovarian cancer. This resistance can be abrogated by specific therapeutic interventions. We are examining NF-kB activation and its pharmacologic inhibition, both in vitro and in vivo, linking laboratory studies to clinical studies with laboratory correlates. The effect of NF-kB activation on resistance to the cytotoxicity of CDDP will be examined. We will delineate the related biologic events associated with acquired CDDP resistance, sensitivity and the association to NF-kB activation. Through transfection experiments, we will examine the transcriptional activator, NF-kB and its effects (positive and negative) on chemotherapy drug sensitivity and resistance. These observations will be extended into new drug development through investigations of new agents including the ansamycin antibiotics, a novel class of agents under development at the MSKCC and the proteosome inhibitor PS-341. Mechanistic studies relating the effect of the inhibitors to drug response are proposed and these effects will be linked to studies of patient derived tissues after investigational drug treatment. This proposal represents a unique opportunity to train fellows in the integration of laboratory studies of acquired drug resistance with the initial clinical studies of new agents which may overcome this mechanism of resistance. Additional laboratory studies related to post transcriptional regulation of TNF-alpha, an important autocrine growth factor for ovarian cancer, are also described. This mechanism is apparently involved in acute CDDP damage response as well. These pilot studies, performed in conjunction with one of the trainees is expected to support additional research in ovarian cancer.