SC-28 * NOVEL INHIBITORS ON HEDGEHOG PATHWAY TO PREVENT MEDULLOBLASTOMA RELAPSE

Abstract

Medulloblastoma (MB) is a highly malignant brain tumor affecting predominantly children. MB arises from cerebella stem cells that do not respond to cellular cues to stop dividing, resulting in them becoming Cancer Stem Cells (CSC). These CSCs are resistant to most conventional chemotherapies, and thus ultimately become the source of tumor relapse. One sub-type of MB harbors a constitutively active Hedgehog (HH) signaling pathway. Recently a large number of HH-inhibitors, mostly that target Smoothened (SMO) have been developed for MB treatment. Unfortunately, one of these inhibitors (vismodegib) also revealed a rapid selection for resistant cells and aggressive relapses likely driven by CSCs. We are focused on alternative targets to SMO for MB- through CSCs eradication. We use mice that spontaneously develop MB: PTCH1+/-p53+/-. It has been described that CSCs isolated from MBs developed on these mice become enriched for genes related to HH signaling. PTCH1+/-p53+/- MB CSCs grown in culture show neuronal stem cells markers, self-renewal, are multipotent and tumorigenic in vivo. We isolated CSCs from these tumors and treated them with a panel of putative inhibitors to identify those that affect CSC survival and self-renewal in vitro, and tumor initiation in vivo. A number of these inhibitors also affect survival of the CD15+ population within the CSCs culture, and abolish its ability to self-renew. Novel drugs acting on HH dependent MB, which do not target SMO, would allow the clinical oncologist to bypass the mechanism of tumor resistance observed in response to SMO antagonists.