SXR as a Therapeutic Target in Drug Resistant Cancer

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DESCRIPTION: (provided by applicant) The Steroid and Xenobiotic Receptor (SXR) is a recently-identified member of the nuclear receptor family of proteins; SXR heterodimerizes with RXR to activate gene transcription. Ligands known to activate SXR include several steroids such as estradiol, progesterone and corticosterone, and drugs such as rifampicin, clotrimazole and nifedipine. The rationale for work in this proposal is based on our observations that: a) taxol, but not taxotere, is a potent activator of SXR; b) SXR is a transcriptional activator of MDR1 and cytochrome P450 3A4 (CYP3A4) expression in human tissues; c) cells treated with known activators of SXR, such as taxol, exhibit a rapid induction of Pgp and CYP3A4 expression resulting in significantly increased rates of chemotherapeutic drug efflux and metabolic inactivation; and d) SXR, Pgp, and CYP3A4 are variably expressed in a range of human tumors. Our data suggests that SXR may be responsible in part for the multiple drug resistance phenotype through a rapid and transient induction of genes required for drug transport and metabolic clearance. We hypothesize that SXR is an important determinant of the MDR phenotype by transiently inducing the genes required for drug detoxification, and that new compounds or strategies designed to block activation of SXR may inhibit the emergence of drug resistance. In testing our hypothesis, we will gain a better understanding of the signaling pathway upstream of CYP3A4, MDR1, and other drug resistance-associated genes, and elucidate whether the inherent inducibility of these genes through SXR is an important mechanism of treatment failure in cancer. Furthermore, the work performed in this proposal will determine if SXR gene expression is elevated in human tumors relative to adjacent normal tissues. If our overall hypothesis is confirmed, new agents which are not ligands for SXR or drugs which block the activation of SXR, will abrogate the emergence of inducible drug resistance in patients with SXR-overexpressing tumors.