Perspectives and Challenges in Molecular-Based Diagnostics and Personalized Treatment for Recurrent High-Grade Gliomas

Abstract

Glioblastoma is the most common and most malignant type of intrinsic brain tumor in adults. The standard of care for glioblastoma consists of surgical debulking followed by combined radiochemotherapy. The clinical efficacy of standard therapies for newly diagnosed glioblastomas is rather modest with the highest survival rate at 5-years being less than 10%. Inevitable recurrence after cytotoxic therapies poses the major challenge in the clinical management of high grade gliomas. For recurrent glioblastomas, there is no standard therapy with lack of level one evidence for treatment efficacy. Recent evidence indicates that post-therapy recurrence in gliomas is a consequence of a plethora of molecular and cellular factors including intratumoural heterogeneity, functional hierarchy of distinct types of glioma cells, dynamic changes in the molecular landscapes and cellular composition of the tumour during therapy and the impact of particular treatment modalities. There is an emerging consensus that molecular distinctions within and between individual tumours is an important factor determining clinical outcomes. Consequently, integrated approaches based on the combination of molecular profiling with traditional methods such as immunohistochemical phenotyping, karyotyping and/or non-quantitative methylation-specific PCR have emerged as a promising venue towards increasing the predictive value of diagnostics for malignant brain tumors. The high level of inter-and intra-tumoural molecular diversity in gliomas underscores the need of integrating high throughput molecular profiling and pharmacogenomics into a diagnostic paradigm for gliomas and raises the possibility that molecular-instructed personalized treatments may provide clinical benefit to patients with glioblastoma, particularly in the setting of post-treatment recurrence. Here we discuss potential prospects and challenges of patient-tailored diagnostics and personalized treatment strategies for recurrent glioblastomas.

Case of multifocal glioblastoma with four fusion transcripts of ALK, FGFR2, NTRK2, and NTRK3 genes stresses the need for tumor tissue multisampling for transcriptomic analysis

“…The elevated level of intrinsic and acquired resistance to the standard therapy is the major cause of short survival in patients with GBM. Advances in understanding the molecular basis of GBM call for rethinking the prospects of the “one-treatment-fits-all” approach and necessitates new concepts for diagnostics, patient stratification, and treatment of GBMs ( Kalasauskas et al 2017 ).…”

New Strategies in Diagnosis and Treatments for Brain Tumors

“…This bioinformatics approach, which can simultaneously analyze the entire transcriptome, will help to achieve an enhanced understanding of complex interactions, which are difficult to understand when concentrating on specific molecules or pathways. It further carries the potential of suggesting effective therapies on an individual basis [11].…”

“…MRI techniques, for example, using FLAIR sequences [14], are among the most promising options. Kinoshita et al compared MRI relaxometry to identify tumor tissue by assessing of cell density to conventional 11 C-Mehtionine PET. The results were validated by stereotactic biopsy and histopathologic workup.…”