Functional Precision Oncology: The Next Frontier to Improve Glioblastoma Outcome?

Abstract

Glioblastoma remains the most malignant and intrinsically resistant brain tumour in adults. Despite intensive research over the past few decades, through which numerous potentially druggable targets have been identified, virtually all clinical trials of the past 20 years have failed to improve the outcome for the vast majority of GBM patients. The observation that small subgroups of patients displayed a therapeutic response across several unsuccessful clinical trials suggests that the GBM patient population probably consists of multiple subgroups that probably all require a distinct therapeutic approach. Due to extensive inter- and intratumoral heterogeneity, assigning the right therapy to each patient remains a major challenge. Classically, bulk genetic profiling would be used to identify suitable therapies, although the success of this approach remains limited due to tumor heterogeneity and the absence of direct relationships between mutations and therapy responses in GBM. An attractive novel strategy aims at implementing methods for functional precision oncology, which refers to the evaluation of treatment efficacies and vulnerabilities of (ex vivo) living tumor cells in a highly personalized way. Such approaches are currently being implemented for other cancer types by providing rapid, translatable information to guide patient-tailored therapeutic selections. In this review, we discuss the current state of the art of transforming technologies, tools and challenges for functional precision oncology and how these could improve therapy selection for GBM patients.

Single-cell molecular profiling using ex vivo functional readouts fuels precision oncology in glioblastoma

“…In order to draw clinically relevant conclusions, a larger cohort of patients/samples will have to be ex vivo evaluated with a PROSPERO-like approach, while integrating additional, predictive clinical parameters such as extent-of-resection/tumor size/location, number of applied therapy cycles, and genomic aberrations. Recently, the first clinical trials have been initiated, whereby cytotoxicity assays as functional readouts are intended to be performed on patient-derived models and ex vivo treated GBM biopsies [6]. Although PDCLs and biopsies are similar, they are not identical [18].…”

Determining the Research Priorities for Adult Primary Brain Tumours in Australia and New Zealand: A Delphi Study with Consumers, Health Professionals, and Researchers

“…A recent systematic review evaluated current molecular and pre-clinical studies, concluding that there is a need for further experimental research in this area [ 31 ]. Additionally, Panovska and Smet [ 32 ] highlight that precision oncology initiatives might improve outcomes for glioblastoma patients.…”

Single-cell molecular profiling using ex vivo functional readouts fuels precision oncology in glioblastoma

“…Already for more than 15 years, the uniformed standard-of-care protocol for GBM has not been changed, despite extensive insights in inter-patient and intra-tumoral heterogeneity 1,3,4 Major efforts over the past 2 decades have aimed at identifying better therapies for GBM, which so far did not lead to substantial changes in overall survival 5 . However, in spite of the overall inability to treat GBM, clinical trials often describe anecdotical or small groups of patients that did show a clinical response 6,7 , suggesting that methods to better identify these exceptional patients could lead to a potentially improved clinical management.…”