NSC PhD Thesis Proposal: Jennifer L. Stripay
Building the Network: Restoration of c-Cbl Function as a Critical Therapeutic Target in Glioblastoma Multiforme that Integrates Multiple Nodes of Cancer Control
Monday, November 4
Advisor: Dr. Mark Noble
Glioblastoma multiforme (GBM) is the most common primary tumor of the central nervous system and is classified as a Grade IV astrocytoma, a status reflective of its potent malignancy and highly undifferentiated state. GBM remains invariably fatal, with an average survival of about 12 months despite multimodal therapy. Oncogenic signaling via growth factor receptor tyrosine kinases (RTK) contributes significantly to the malignancy of GBM, with more than 50% of cases exhibiting amplification of RTK signaling, often in the absence of genetic alterations. Much of the current research in therapeutic development is focused on targeting individual hallmarks of GBM, such as individual RTKs. A more effective intervention strategy, however, might be to target points of convergence between these different features. We have found that malignant tumor cells exhibit dysregulation of recruitment and function of the E3 ubiquitin ligase c-Cbl, a critical regulator of the trafficking of RTKs for degradation, and that dysfunction of the redox/Fyn/c-Cbl (RFC) pathway is a critical regulator of multiple aspects of GBM biology. In addition to addressing restoration of normal c-Cbl function via modulation of its inhibitory binding partners, this proposal investigates the possibility that dysfunction of the RFC offers an opportunity to simultaneously target multiple critical control points in GBM biology. Moreover, we have identified several FDA-approved drugs that restore c-Cbl function. These c-Cbl activity-enhancing compounds modulate a network of malignant hallmarks in GBM (including the cancer stem cell niche, the heat shock response pathway, and autophagocytosis) and represent a clinically attractive approach in the treatment of GBM.
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