BRAIN TUMOUR INITIATING CELLS AND TARGETING STAT3 ONCOGENIC SIGNALLING IN GBM

BACKGROUND: Glioblastoma (GBM) is a devastating disease and the most lethal of adult brain tumours. Despite standard surgery, radiation and chemotherapy, the median survival is 15 months, thought to be due, in part, to recurrence from a small reservoir of brain tumour initiating cells. Our laboratory discovered adult neural stem cells, now found to be present in the brains of all adult mammals, through the development of the clonal neurosphere assay. This assay has contributed to the identification of adult human brain tumour initiating cells (BTICs), which may represent a reservoir that leads to GBM recurrence and death. Building upon the identification of growth factors and cytokines that converge on the cytoplasmic signal transducer and activator of transcription 3 (STAT3) to maintain the adult neural stem cell undifferentiated state, and the fact that STAT3 is abnormally active in GBM and may be one of the causes of tumour growth and therapeutic resistance, targeting the janus kinase (JAK)/STAT3 signalling pathway has become a major research focus for our laboratory. Here, we report the GBM translational potential of R333, a JAK/SYK inhibitor in development for other indications by Rigel Pharmaceuticals. METHODS: We have developed a cellular resource of more than 100 BTIC lines derived from GBM patients. Collaborative studies with academic and industry partners has resulted in the identification of promising therapeutic candidates that target JAK/STAT3 signalling in GBM. These compounds are tested for their ability to attenuate growth of BTICs in cell culture, on target activity in vitro and in vivo, and for their impact on the the survival of immunocompromised mice that have received BTIC xenografts. We employed this approach to examine the therapeutic potential of R333. RESULTS: In a collection of diverse patient-derived BTIC lines, R333 demonstrated potent, on-target JAK/STAT3 inhibition at low micromolar doses that effectively decreased BTIC viability and clonogenic potential, without affecting human fetal astrocytes. Importantly, R333 could be co-administered with temozolomide without reducing therapeutic response. Using phosphoproteomics, we confirmed the primary target of R333 in BTSCs as activated STAT3. In a BTIC orthotopic xenograft model, systemic treatment with R348, the pro-drug form of R333, resulted in BBB penetration and significant increased overall median survival without major side effects. CONCLUSIONS: These data suggest that R333 (R348) is a potent, BBB-permeable JAK/STAT3 inhibitor, worthy of further clinical evaluation for GBM treatment. These findings support our overall hypothesis that targeting the STAT3 signalling pathway may represent an effective therapeutic approach to managing GBM. SECONDARY CATEGORY: Tumor Biology.

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