Glioblastoma and the search for non-hypothesis driven combination therapeutics in academia

Glioblastoma (GBM) remains a cancer of high unmet clinical need. Current
standard of care for GBM, consisting of maximal surgical resection, followed by
ionisation radiation (IR) plus concomitant and adjuvant temozolomide (TMZ),
provides less than 15-month survival benefit. Efforts by conventional drug
discovery to improve overall survival have failed to overcome challenges
presented by inherent tumor heterogeneity, therapeutic resistance attributed to
GBM stem cells, and tumor niches supporting self-renewal. In this review we
describe the steps academic researchers are taking to address these limitations in high throughput screening programs to identify novel GBM combinatorial targets.
We detail how they are implementing more physiologically relevant phenotypic
assays which better recapitulate key areas of disease biology coupled with more
focussed libraries of small compounds, such as drug repurposing, target discovery, pharmacologically active and novel, more comprehensive anti-cancer targetannotated compound libraries. Herein, we discuss the rationale for current GBM combination trials and the need for more systematic and transparent strategies for identification, validation and prioritisation of combinations that lead to clinical trials. Finally, we make specific recommendations to the preclinical, small compound screening paradigm that could increase the likelihood of identifying tractable, combinatorial, small molecule inhibitors and better drug targets specific to GBM.