Identifying the mechanism of vulnerability to MLN4924 in glioblastoma
Glioblastoma (GBM) is the most common form of adult brain cancer with a median survival of just fourteen months. The current standard of care for GBM is surgical resection followed by radiation and chemotherapy (Temozolomide, TMZ). Despite decades of research, there are no targeted therapies available for the treatment of GBM.
Neddylation is a post-translational mechanism that marks proteins for degradation through activity of NEDD8 Activating Enzyme (NAE). NAE blocks cullin-RING ligases from initiating proteosomal degradation of select substrates including cell cycle regulators and apoptosis modulators. MLN4924 targets NAE, inhibits neddylation, and subsequently induces apoptosis in cancer cells. We have discovered a cohort of GBM patient derived xenograft (PDX) models that demonstrate differential sensitivity when treated with MLN4924, suggesting there may be a context of vulnerability to MLN4924 treatment in GBM. Most pertinently, the effects we observe are in a PDX cultured as 3D neurospheres that more closely resemble the true tumor architecture, heterogeneity, and “stem-like” phenotype characteristic of tumor growth. By investigating the mechanism of vulnerability to MLN4924 in GBM PDX cell lines we hope to identify a molecular signature that is associated with a subset of GBMs vulnerable to MLN4924. As the treatment options for GBM are extremely limited, this may highlight a novel alternative opportunity to treat a subset of patients with this aggressive disease.