Informing development of brain cancer therapies within "preclinical trials" using ex vivo patient tumors

Brain and nervous system cancers account for only ∼1.3% of new cancer diagnoses but rank ninth in US cancer mortality, a disparity partly driven by limited therapeutic options and inadequate preclinical models that misrepresent a drug's therapeutic potential. Considering that about 90% of drugs validated with these models fail in late-phase clinical trials, it is imperative to further scrutinize drugs in preclinical settings that better model relevant aspects of disease and treatment response. New paradigms must account for challenges unique to brain cancers such as lack of relevant biomarkers and both intra-disease and patient to patient heterogeneity, which cause treatments to be effective in a suboptimal proportion of the population. In this review, we investigate the current brain cancer drug development landscape, introduce a growing field of functional precision medicine, and propose the inclusion of "preclinical trials" that interrogate the effects of new therapies and drug delivery mechanisms on living patient tumors ex vivo. These preclinical trials respond to the FDA's recent announcement to phase out and replace live animal testing with human-based lab models. Functional models can address heterogeneity and biomarker identification through accrual of living patient tumor tissue, preclinical drug sensitivity testing, identification of non-responders and resistance mechanisms, and development of functional predictive biomarkers and companion diagnostics. Because functional precision medicine stratification of clinical trials candidates has shown improved clinical trials outcome, using this paradigm earlier in drug development could enhance clinical trial success, leading to more FDA-approved drugs and therapeutic options for brain cancer patients.