Abstract B14: Targeting a network of cancer control nodes through rescue of c-Cbl: A novel therapeutic approach in GBM

Glioblastoma multiforme is the most common primary brain tumor in adults, the most malignant of all intracranial tumors, and is associated with inevitable recurrence and 15 month mean survival despite multimodal therapy. The majority of GBM tumors maintain heterogeneous amplifications (many in the absence of genetic mutation) in receptor tyrosine kinases (RTKs), which are mediators of growth factor signaling. Our lab has discovered that control over RTK levels in normal CNS progenitors is maintained by the Redox/Fyn/c-Cbl (RFC) pathway whereby increased oxidative state results in activation of the E3 ubiquitin ligase c-Cbl and the subsequent internalization and degradation of target RTKs. RFC signaling is disrupted in GBM due to a physical sequestration of c-Cbl, preventing pro-oxidative chemotherapeutics from reducing pro-survival signaling through Epidermal Growth Factor Receptor, Platelet-Derived Growth Factor Receptor, etc. Using a triangulating drug screen, we identified candidate FDA-approved small molecules capable of reducing signaling downstream of c-Cbl-targeted RTKs. We found that candidate URMC-06, an antidepressant with a good clinical safety profile, could rescue RFC signaling and significantly enhance the sensitivity of GBM cells to a pro-oxidative agent (Tamoxifen) in a c-Cbl-dependent manner. There is significant evidence to suggest that a tumor initiating cell population mediates the malignancy of GBM tumors. These cells express stem-cell associated markers and exhibit self-renewal capacity. We observed a c-Cbl-dependent inhibition of neurosphere formation (an in vitro measure of self-renewal) and a reduction in the expression of stem cell markers Sox2, beta-catenin, FoxM1 and Nestin in GBM cells treated with URMC-06. Our candidate also facilitated reduction in heat shock signaling and an inhibition of autophagy (both putative survival mechanisms) in GBM cells. URMC-06 was effective, in combination with clinically relevant agents (Temozolomide and Tamoxifen), at reducing tumor progression in an in vivo xenograft model of GBM. Our work supports the hypothesis that c-Cbl is a critical player in GBM that integrates multiple nodes of cancer control and that pharmacological rescue of c-Cbl represents a potentially powerful therapeutic approach. Citation Format: Jennifer L. Stripay, Brett M. Stevens, Addie L. Bardin, Mark D. Noble. Targeting a network of cancer control nodes through rescue of c-Cbl: A novel therapeutic approach in GBM. [abstrac