gdc-0152 and Glioblastoma

In glioblastomas, apoptosis inhibitor proteins (IAPs) are involved in apoptotic and nonapoptotic processes. We previously showed that IAP inhibition induced a loss of stemness and glioblastoma stem cells differentiation by activating nuclear factor-κB under normoxic conditions. Hypoxia has been shown to modulate drug efficacy. Here, we investigated how IAPs participate in glioblastoma stem-like cell maintenance and fate under hypoxia. We showed that in a hypoxic environment, IAPs inhibition by GDC-0152, a small-molecule IAPs inhibitor, triggered stem-like cell apoptosis and decreased proliferation in four human glioblastoma cell lines. We set up a three-dimensional glioblastoma spheroid model in which time-of-flight secondary ion mass spectrometry analyses revealed a decrease in oxygen levels between the periphery and core. We observed low proliferative and apoptotic cells located close to the hypoxic core of the spheres and glial fibrillary acidic protein

Topics: Adaptor Proteins, Signal Transducing; Adrenomedullin; Apoptosis; Baculoviral IAP Repeat-Containing 3 Protein; Brain Neoplasms; Carbonic Anhydrase IX; Cell Differentiation; Cell Hypoxia; Cell Line, Tumor; Cell Proliferation; Cyclohexanes; Enzyme Inhibitors; Gene Expression Regulation, Neoplastic; Glioblastoma; Humans; Inhibitor of Apoptosis Proteins; Neoplasm Proteins; Neoplastic Stem Cells; Oxygen; Pyrroles; Signal Transduction; Spheroids, Cellular; Tissue Culture Techniques; X-Linked Inhibitor of Apoptosis Protein

Glioblastomas (GBMs) are the most aggressive primary brain tumors in adult and remain a therapeutic challenge. Targeting key apoptosis regulators with the ultimate aim to restore apoptosis in tumor cells could be an interesting therapeutic strategy. The inhibitors of apoptosis proteins (IAPs) are regulators of cell death and represent attractive targets, especially because they can be antagonized by SMAC mimetics. In this study, we first investigated the expression of cIAP1, cIAP2, XIAP and ML-IAP in human GBM samples and in four different cell lines. We showed that all GBM samples and GBM cell lines expressed all these IAPs, although the expression of each IAP varied from one case to another. We then showed that high level of ML-IAP predicted worse progression-free survival and overall survival in both univariate and multivariate analyses in two independent cohorts of 58 and 43 primary human GBMs. We then used GDC-0152, a SMAC mimetic that antagonizes these IAPs and confirmed that GDC-0152 treatment in vitro decreased IAPs in all the cell lines studied. It affected cell line viability and triggered apoptosis, although the effect was higher in U87MG and GL261 than in GBM6 and GBM9 cell lines. In vivo, GDC-0152 effect on U87MG orthotopic xenografts was dose dependent; it postponed tumor formation and slowed down tumor growth, significantly improving survival of GBM-bearing mice. This study revealed for the first time that ML-IAP protein expression correlates with GBM patient survival and that its antagonist GDC-0152 improves outcome in xenografted mouse.

Topics: Adult; Aged; Aged, 80 and over; Animals; Cell Line, Tumor; Cell Proliferation; Cell Survival; Chromatography; Cyclohexanes; Glioblastoma; Humans; Immunohistochemistry; Inhibitor of Apoptosis Proteins; Mice, Nude; Middle Aged; Molecular Targeted Therapy; Paraffin Embedding; Prognosis; Pyrroles; Tissue Fixation; Young Adult