Significance of the Prolactin Receptor in Glioblastoma

Compounds blocking the prolactin receptor (PRLR) have not yet reached the clinic. There are however several observations supporting a future use of PRLRA for tumor treatments. In particular, this could be the case for treatment of glioblastoma (GBM). We have previously developed a recombinant protein that blocks the PRLR and our goal is to link this protein with established drugs used for GBM treatment. The idea is to use receptor internalization to enrich a drug of interest in the target cells in addition to provide a growth inhibitory effect of the antagonist alone. TSC proteins suppress the mTOR pathway and the discovery that certain tumors have lost TSC functionality immediately suggested how to treat the over-activity of mTOR in some cancers. Rapamycin is a clinical drug blocking mTOR and it has been used for many years as an immune suppressant. The use of Rapamycin in cancer treatment, although it does not provide a cure, serves to slow down tumor progression. A further problem with Rapamycin is related to the immunosuppressing activity of this drug. We found an interesting connection between the PRL system and some forms of tumors. In essence, we observed that PRLR levels commonly is increase in different type of tumors including GBM. This provides a rationale to use PRLRA for two reasons (1) to reduce PRL induced growth by blocking the PRLR, JAK-STAT/AKT-PI3 pathways and (2) to use the PRLR to deliver Rapamycin preferentially to GBM cells.