NF-KB as Mediator of Drug Resistance

The experimental hypothesis of this part of our work is that the activation of NF-kB DNA binding is a common feature of acquired CDDP resistance in ovarian cancer. In this work, we are examining NF-kB activation and its pharmacologic inhibition, both in vitro and in vivo, linking laboratory studies (aims 1 and 3) to clinical studies (aims 2 and 4) with laboratory correlates. The effect of NF-kB activation on resistance to the cytotoxicity of CDDP paclitaxel, melphalan, doxorubicin, topotecan and other agents 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-kBand its effects (positive and negative) on chemotherapy drug sensitivity and resistance. These observations will be extended into new drug development through investigations of the ansamycin antibiotics, a novel class of agents under development at the MSKCC and the proteasome inhibitor PS-341. Mechanistic studies relating the effect of the inhibitors to drug response are plannedand these effects will be linked to studies of patient derived tissues after investigational drug treatment. The current objectives are: Specific Aim 1: To examine the role of NF-kB in acquired chemotherapy resistance in vitro, including the spectrum of resistance, the activation process and the cellular consequences of increased NF-kB activity. Specific Aim 2: To explore the in vivo association between the IkB / IkB kinase and CDDP resistance in tissues from patients with ovarian cancer. Specific Aim 3: To explore the effect and mechanism of two potential clinical inhibitors of NF-kB activation (Herbimycin A and PS-341) on chemotherapy sensitivity in vitro. Specific Aim 4: To perform clinical trials of two new agents PS-341 and 17 allylaminogeldanamycin and examine the association between increased NF-kB activity, decreased IkB levels and CDDP resistance in vivo for women with ovarian cancer. This project represents integration of laboratory studies of NF-kB mediated acquired drug resistance with the early clinical studies of two new agents which may overcome this mechanism of resistance in patients with advanced cancer.