Project 2: Targeting metabolic vulnerabilities in glioblastoma

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Epidermal growth factor receptor (EGFR) signaling regulates the metabolism to fuel the biosynthetic and bioenergetic processes necessary for glioblastoma (GBM) growth and survival. In Project 2 of UCLA Brain SPORE, we hypothesize that therapeutically exploiting this relationship with rationally-selected targeted therapies will lead to increased tumor control.

Aim 1 will evaluate whether targeting EGFR-driven glucose metabolism – with EGFR tyrosine kinase inhibitors (TKIs) – creates a vulnerable metabolic state for the tumor, thereby rendering GBM xenografts synergistically susceptible to pharmacological p53 activation (e.g., with idasanutlin).

Aim 2 seeks to explore the mechanism underlying the synergistic lethality of combined targeting of EGFR-driven glucose metabolism and p53 in GBM.

Finally, Aim 3 will evaluate whether this novel combination is safe in GBM patients, while also obtaining preliminary efficacy data.  Included in this clinical study is the evaluation of whether rapid changes in glucose uptake in vivo – as measured with 18F-FDG PET – is predictive of therapeutic outcome in GBM patients.  Collectively, these studies hope to provide a new treatment paradigm, coupled with non-invasive biomarker, for selectively targeting and exploiting GBM metabolism as a means to the improve the outcomes for GBM patients.