Precision oncology : oncogenic stat3 signalling in brain tumours

• Main Author: Tan, Melanie Si Yan
• Other Authors: Tan Nguan Soon, Andrew
• Format: Theses and Dissertations
• Language: English
• Published: 2019
• Subjects: Science::Biological sciences::Human anatomy and physiology::Neurobiology; Science::Biological sciences::Molecular biology
• Online Access: https://hdl.handle.net/10356/82741; http://hdl.handle.net/10220/49094
• Institution: Nanyang Technological University

Brain tumour patients diagnosed with grade IV glioblastoma often show dismal prognosis despite the standard of care chemo- and radiation therapies. The Cancer Genome Atlas effort demonstrated that transcriptomic profiles distinguish three glioma-intrinsic subtypes, each with unique genetic aberrations and prognosis. While significant effort has been made to characterize glioblastomas based on their molecular content, functional or biological validation remains lacking. STAT3 activation represents the final molecular switch that precedes transition into the highly aggressive, recurrent mesenchymal subtype. Furthermore, there are several STAT3 small molecule inhibitors in clinical trials for solid malignancies. Our work provides an insight into STAT3 stratification in GBM using our unique STAT3 functionally-tuned gene signature. We show that this gene signature stratifies GBM patients, and is not confounded by current clinical and molecular classification. To provide preclinical evidence that stratification leads to more effective STAT3-targeted treatment outcomes, we applied this signature to our collection of tumour cells with matched primary and xenograft tumour molecular information. We identified STAT3-sensitive and -resistant tumours, and validated STAT3 dependence in vitro using pharmacologically-treated and genetically manipulated, matched GBM cells. We validated responsiveness to STAT3 inhibition through in vitro and animal experimentation. Importantly, by analysing up-regulated genes in the STAT3-resistant profile, corroborated by our kinome screen data, dual inhibition of IGF-1R and STAT3 presents a viable strategy to sensitize this cohort. Our study highlights the importance of patient stratification for the utility of STAT3 inhibitors in GBM. This represents a new paradigm challenging the current use of morphological methods such as histology to diagnose and subsequently treat patients.