DEVELOPMENT OF GLIEXP; A HIGH-THROUGHPUT EX VIVO DRUG SCREENING PLATFORM FOR GLIOBLASTOMA

Abstract

Abstract AIMS With diminishing returns and common clinical failure rates from traditional preclinical and animal-based drug discovery strategies, emphasis is being placed on alternative drug discovery platforms, such as ex vivo approaches. Such approaches represent a departure from both preclinical animal-based models and more traditional clinical-based strategies and aim to address intra/inter-patient variability at an earlier stage of drug discovery. Additionally, they could also offer precise treatment stratification for patients within a week of surgery to direct a tailored treatment course. One tumour group that could significantly benefit from such ex vivo approaches are high-grade gliomas, which exhibit extensive heterogeneity, cellular plasticity and therapy- resistant glioma stem cell (GSC) niches, and where historic preclinical models have failed to generate new therapies leading to 50-year stagnant dire survival rates of around 15 months post-diagnosis. METHOD We have developed and optimized a high-throughput ex vivo drug screening platform; GliExP, which maintains GSC populations using immediately dissociated fresh surgical tissue. RESULTS As a proof-of-concept for GliExP, we have optimized standard-of-care chemoradiotherapy responses which can correctly predict MGMT status based on Temozolomide sensitivity. We have screened 30+ small molecule therapeutics and preclinical compounds against 18 different patient’s tumours, including multi-region spatial het- erogeneity sampling from several individual tumours. Drug responses are further correlated to transcriptomic and genetic profiles. CONCLUSIONS Our data provides a strong basis to build upon GliExP to incorporate combination-based oncology therapeutics in tandem with standard-of-care therapies as an important preclinical model to triage experimental therapeutics for clinical translation, delivering rapid identification of effective treatment strategies for individual gliomas.