Professor Murray Norris
We have previously shown that the MYCN oncogene and the Multidrug Resistance-associated Protein 1 (MRP1/ABCC1) gene are both critically important in neuroblastoma and are powerful prognostic markers of poor outcome. As such, they represent valuable targets for the development of novel therapeutics through the generation of specific small-molecule inhibitors.
We have recently demonstrated that another ABCC/MRP family member, ABCC4/MRP4, is also an extremely powerful independent predictor of neuroblastoma outcome. Although this drug transporter is able to expel chemotherapeutics from tumour cells, our data suggest that ABCC4/MRP4 makes a fundamental contribution to the malignant phenotype of neuroblastoma independent of drug exposure. We are currently investigating in more detail precisely how ABCC4/MRP4 contributes to highly malignant neuroblastoma using a range of experimental approaches.
Since siRNA-mediated silencing of ABCC4/MRP4 dampens neuroblastoma cell proliferation and induces a more differentiated cellular morphology, we expect that therapeutic targeting of ABCC4/MRP4 will be of clinical benefit for this disease, as well as for other cancers expressing high ABCC4/MRP4 levels. Therefore we are using high-throughput screening of chemical libraries to generate novel inhibitors of ABCC4/MRP4.
External collaborators: Andrei Gudkov (Roswell Park Cancer Institute, USA), Catherine Burkhart (Cleveland BioLabs Inc, USA)