Evaluating the efficacy of Casein Kinase 1 Agonists on Medulloblastoma Recurrence

Jezabel Rodriguez-Blanco, Ph.D. Postdoctorate Associate, Molecular Oncology The DeWitt Daughtry Family Department of Surgery

Progress Update: 9/2013-8/2015

Medulloblastoma (MB) is a highly malignant brain tumor affecting predominantly children. MB arises from granular progenitors that after cerebella development do not respond to cellular cues to stop functioning, resulting in them becoming cancer stem/progenitor cells (CSC) that drive tumor progression. Such CSCs are thought to be resistant to most conventional chemotherapies, and thus ultimately become the source of tumor relapse. MB CSCs harbor activated developmental signaling pathways, and two of these are also involved in more than 45 % of MBs: Hedgehog (HH) and Wingless (WNT). Recently, a large number of HH-inhibitors, mostly those targeting the pivotal component Smoothened (SMO), have been developed for MB treatment. Unfortunately, clinical trials of one of these SMO inhibitors, vismodegib, also revealed a rapid selection for vismodegib resistant cells and aggressive relapses likely driven by CSCs. Our work is focused on finding alternative targets to SMO for MB CSCs eradication. We are using a genetic mouse model that spontaneously develops MB (PTCH1+/- p53-/- ). CSCs isolated from such mice were previously shown to harbor both activated HH and WNT signaling pathways. We have isolated these CSCs and now show that when grown in culture they elaborate neuronal stem cells markers and can differentiate into multiple neuronal lineages. Further, they exhibit the capacity to self renew, as well as the ability to form new tumors when injected into immunocompromised mice. These CSCs were treated with an agonist to Casein Kinase1a (CK1a), a shared component of both the WNT and HH signaling pathways. The effect of this inhibitor on CSC cells attenuated progenitor cell proliferation, as well as their survival and self-renewal in vitro, and their ability to form new tumors in vivo. The encouraging effect of this class of small-molecule inhibitor of the HH and WNT signaling path-ways on MB CSCs, suggests they it may function as an alternative to SMO inhibitors for which clinically relevant mechanisms of resistance have already emerged!

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